Camrelizumab plus apatinib in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia (CAP 01): a single-arm, open-label, phase 2 trial.

BACKGROUND: Treatment options for patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia are scarce. The synergistic antitumour effect of immunotherapy and antiangiogenic drugs has been shown in many solid tumours. This phase 2 trial evaluated the activity and safety of camrelizumab (PD-1 inhibitor) plus apatinib (VEGF receptor inhibitor) in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia. METHODS: This was a single-arm, open-label, phase 2 trial, done at a single tertiary health-care centre in Beijing, China. Women (18-70 years) with high-risk (International Federation of Gynecology and Obstetrics score ≥7) chemorefractory or relapsed gestational trophoblastic neoplasia who had received at least two lines of previously unsuccessful multidrug chemotherapy regimens and had an Eastern Cooperative Oncology Group performance status of 0-2 were eligible for inclusion. Patients received 4-week cycles of intravenous camrelizumab 200 mg every 2 weeks plus oral apatinib 250 mg once per day until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed according to serum human chorionic gonadotrophin concentration. Activity and safety were analysed in all patients who received at least one dose of study drug. The study is ongoing, but recruitment is complete. The study is registered with ClinicalTrials.gov, NCT04047017. FINDINGS: Between Aug 7, 2019, and March 18, 2020, 20 patients enrolled; 19 (95%) were diagnosed with choriocarcinoma and one (5%) had placental site trophoblastic tumour. The median follow-up duration was 18·5 months (IQR 14·6-20·9). The objective response rate was 55% (95% CI 32-77); ten (50%; 95% CI 27-73) patients had complete response. The most common grade 3 treatment-related adverse events were hypertension (five [25%] patients), rash (four [20%] patients), neutropenia (two [10%]), leukocytopenia (two [10%]), and aspartate aminotransferase increase (two [10%]). One patient had a treatment-related serious adverse event (aspartate aminotransferase 19-times higher than the upper limit of normal). No grade 4 or 5 treatment-related adverse events were reported. INTERPRETATION: Camrelizumab plus apatinib showed promising antitumour activity and acceptable toxicity and could be a salvage therapy option for the treatment of high-risk chemorefractory or relapsed gestational trophoblastic neoplasia. Immune checkpoint inhibitors combined with chemotherapy for heavily-treated patients and upfront use of camrelizumab plus apatinib for patients with high-risk gestational trophoblastic neoplasia are under investigation in phase 2 trials. FUNDING: National Natural Science Foundation of China, Jiangsu Hengrui Pharmaceuticals.

Outcomes of minimally invasive versus open abdominal hysterectomy in patients with gestational trophoblastic disease.

OBJECTIVE: The aim of this study is to compare surgical and oncologic outcomes for women undergoing MIH or open abdominal hysterectomy (OAH) for management of gestational trophoblastic disease (GTD). METHODS: Patients who underwent hysterectomy for GTD between January 1, 2009 and December 31, 2018 were identified using an institutional database and tumor registry. Patients were stratified based on indication for and mode of hysterectomy. RESULTS: 39 patients underwent hysterectomy for GTD - 22 MIH and 17 OAH. 26 hysterectomies (66.7%) were performed for primary treatment of GTD, 7 (17.9%) for chemoresistance, 2 (5.1%) for uterine hemorrhage, and 4 (10.3%) for other indications. Mean tumor size (4.2 vs 4.6 cm; p = .81) and operative time (136 vs 163 mins; p = .42) were similar in both groups. MIH was associated with significantly less blood loss (71.5 vs 427.3 ml; p = .03) and shorter hospital stay (1.5 vs 3.9 days, p = .02) than OAH. Postoperative histology comprised 12 complete moles (6 invasive), 8 choriocarcinomas, 9 placental site trophoblastic tumors and 9 epithelioid trophoblastic tumors. Median follow-up was 67.2 months (50.2 MIH, 79.3 OAH; range 11.1-131.2) and there was no difference in remission (81.8% MIH vs 76.5% OAH; p = .68). There were 7 recurrences (4 MIH, 3 OAH) and 3 deaths (2 MIH, 1 OAH). Overall survival was 97.3% at 2 years and 88.5% at 5 years. There was no significant difference in 5-year survival by mode of surgery (MIH 90.9%, OAH 83.3%; p = .40). CONCLUSIONS: Patients undergoing MIH at our centers have similar oncologic outcomes, lower surgical blood loss and shorter hospital stay compared to those undergoing OAH. Overall survival is similar regardless of mode of surgery.

Validation of an online tool for early prediction of the failure-risk in gestational trophoblastic neoplasia patients treated with methotrexate.

PURPOSE: In a low-risk gestational trophoblastic neoplasia (GTN) treated with methotrexate (MTX), the modeled hCG (human chorionic gonadotropin) residual concentration (hCGres), calculated with NONMEM program® (NM) during the first 50 treatment days, is a predictor of MTX-resistance risk. This model was implemented with another algorithm on https://www.biomarker-kinetics.org/hCG . The objective was to confirm the validity of the website estimations with respect to NM. METHODS: The consistencies of modeled hCGres estimated by NM and by the website were assessed in a dataset of 60 fictive patients with simulated hCG profiles, as well as in an independent database of 531 actual patients. Moreover, the hCGres predictive values regarding MTX failure-risk were assessed. RESULTS: The values of hCGres obtained with both methods were highly consistent in the fictive patient and in the actual patient datasets: median relative prediction errors (RPE) were - 0.059 and 9.9 × 10-7, respectively. The ROC AUCs for predictions of MTX failure-risk were 0.90 (95% CI 0.87,0.93) with both NM and the website. The gradual association between increasing hCGres and the 2-year MTX failure-free survival was confirmed. CONCLUSION: There is a high consistency of hCGres estimates obtained with the two methods. The website is meant to help clinicians in the interpretation of hCG decline curves of MTX-treated GTN patients. hCGres is now validated for more than 1690 patients in four independent datasets, and its recognition as an early predictor of MTX resistance for treatment adjustment and for the future studies should be considered.

Gestational trophoblastic neoplasia lethality among Brazilian women: A retrospective national cohort study.

OBJECTIVE: To investigate GTN lethality among Brazilian women comparing cases of death by GTN with those who survived, thereby identifying factors associated with GTN lethality. METHODS: We retrospectively reviewed medical records of women with GTN treated at ten Brazilian GTN Reference Centers, from January 1960 to December 2017. We evaluated factors associated with death from GTN and used Cox proportional hazards regression models to identify independent variables with significant influence on the risk of death. RESULTS: From 2186 patients with GTN included in this study, 2092 (95.7%) survived and 89 (4%) died due to GTN. When analyzing the relative risk (RR), adjusted for WHO/FIGO score, patients with low risk disease had a significantly higher risk of death if they had choriocarcinoma (RR: 12.40), metastatic disease (RR: 12.57), chemoresistance (RR: 3.18) or initial treatment outside the Reference Center (RR: 12.22). In relation to patients with high-risk GTN, these factors were significantly associated with death due to GTN: the time between the end of antecedent pregnancy and the initiation of chemotherapy (RR: 4.10), metastatic disease (RR: 14.66), especially in brain (RR: 8.73) and liver (RR: 5.76); absence of chemotherapy or initial treatment with single agent chemotherapy (RR: 10.58 and RR: 1.81, respectively), chemoresistance (RR: 3.20) and the initial treatment outside the Reference Center (RR: 28.30). CONCLUSION: The risk of mortality from low and high-risk GTN can be reduced by referral of these patients to a Reference Center or, if not possible, to involve clinicians in a Reference Center with consultation regarding management.

Emergency Etoposide-Cisplatin (Em-EP) for patients with germ cell tumours (GCT) and trophoblastic neoplasia (TN).

BACKGROUND: Etoposide (E) at 100 mg/m2 combined with Cisplatin (P) at 20 mg/m2 represents an induction 2-day regimen embedded in our clinical practice for patients with advanced GCT or TN at high risk of early death. We evaluated 24/7 Em-EP administration to a combined GCT-TN cohort at our Emergency Cancer Treatment Centre (ECTC) to determine its efficacy within the acute setting. METHODS: Patients who received Em-EP during a five-year interval were identified from electronic databases at Imperial College Healthcare NHS Trust. Data collected included demographics, treatment details and clinical outcome. RESULTS: Em-EP was administered in the emergency setting to 104 patients, predominantly young adults (median age 35, range 17-71). Half the cases were GCT (n = 52): 22 male (6 seminomas, 13 non-seminomas); 30 female (2 dysgerminomas, 28 non-dysgerminomas). The other 50% were treated for TN (n = 52): 45 gestational (GTN) and 7 non-gestational. Most patients received Em-EP for a new cancer diagnosis (n = 100, 96%), within 24 h (n = 93, 89%) and out-of-hours (n = 74, 70%). Indications for Em-EP included symptomatic disease (n = 66, 63%), high-burden disease, (n = 51, 49%) and organ failure requiring Intensive Care Unit support (n = 9, 9%). Neutropenic sepsis was observed in 5%. Four-week overall survival after Em-EP administration was 98%. CONCLUSIONS: Despite the potentially fatal complications encountered in the acute setting, early mortality with Em-EP is low at our ECTC. Specialist units that treat unwell patients with advanced GCT or TN should consider making Em-EP available 24/7 for emergency administration. Its efficacy within a prospective cohort and in other platinum-sensitive malignancies requires evaluation.

Complete Resection Is Essential in the Surgical Treatment of Gestational Trophoblastic Neoplasia.

OBJECTIVE: The aim of this study was to determine the utility of surgery in patients with gestational trophoblastic neoplasia (GTN). MATERIALS AND METHODS: We performed a retrospective institutional review board-approved analysis of all patients with GTN at a single institution from 1985 to 2015 and compared all patients who underwent surgery as definitive management for their disease to a matched cohort of those who did not. Kaplan-Meier curves were used to estimate progression-free survival (PFS) and overall survival (OS). RESULTS: Sixty-nine patients underwent a total of 94 surgeries as definitive treatment for GTN. Nineteen patients had multiple surgeries. Progression-free survival and OS were improved in patients with complete macroscopic surgical resection (n = 61) compared with patients with gross residual disease (n = 33) (median PFS 91.2 months vs 3.3 months, and median OS not reached at 108.8 months vs 66.3 months, respectively; P < 0.05). The nature of the surgery (emergent vs planned) and site of metastatic disease did not influence PFS or OS. Of the 61 patients with no visible residual disease, 17 received adjuvant chemotherapy and 44 did not; there were no observed differences in PFS or OS. Patients who underwent surgery as part of definitive treatment (n = 69 patients) were compared with patients with GTN over the same period who received chemotherapy alone (n = 33 patients). Median PFS was improved in the surgical group (5.9 vs 5.1 months, P < 0.01), but OS was not significantly different (P = 0.37). CONCLUSIONS: Complete resection results in improved outcomes in patients who undergo surgery for GTN, whether emergent or planned, independent of disease site, and should be considered as an important component of treatment in some situations.

[Clinical outcome of patients with gestational trophoblastic neoplasia receiving primary treatment at Peking Union Medical College Hospital: a 30-year retrospective cohort study].

Objective: To summarize and analyze the clinical outcomes of gestational trophoblastic neoplasia (GTN) patients receiving primary treatment at Peking Union Medical College Hospital from 1985 to 2015, and investigate the changes in treatment efficacy between the first and the second 15 years. Methods: Clinical data of GTN patient receiving primary chemotherapy at Peking Union Medical College Hospital from January 1985 to December 2015 were retrospectively analyzed. It further compared the therapeutic results and chemotherapy cycles given to GTN patients, according to International Federation of Gynecology and Obstetrics (FIGO, 2000) prognostic score system, who were classified to different stages and low- or high-risk groups. Results: In total, 1 711 GTN patients were included in this study. Comparing the 1985-2000 group and the 2001-2015 group, the results showed that: (1) while the overall complete remission (CR) rate was 93.7% (1 603/1 711) , the CR rate of 2001-2015 group was significantly higher than that of 1985-2000 group [98.4% (1 155/1 174) vs 83.4% (448/537) , χ(2)=139.353, P<0.01]. This difference was significant between stage Ⅲ and Ⅳ patients, but nonexistent between stage Ⅰ and Ⅱ patients, including low- and high-risk groups. (2) The relapse rate of patients who had been in CR was 2.7% (43/1 603) , with no significant differences between the groups of 1985-2001 and 2001-2015 [3.6% (16/448) vs 2.3% (27/1 155) , χ(2)=6.867, P=0.142]. (3) The overall mortality rate was 2.6% (44/1 711) , which significantly decreased in 2001-2015 group compared to 1985-2000 group [1.6% (19/1 174) vs 4.7% (25/537) , χ(2)=13.830, P<0.01]. This difference appeared only in high-risk patients with stage Ⅲ disease (χ(2)=9.505, P<0.01) . (4) Fluorouracil was gradually replaced by floxridine in chemotherapy regimens. The total cycles of chemotherapy regimens given to low-risk patients with stage Ⅲ disease significantly decreased in 2001-2015 group, but no statistical difference was shown with patients at other stages. Moreover, the cycles of consolidation treatment were significantly reduced in patients with stage Ⅲ patients. Conclusions: GTN patients could obtain satisfactory curative results after appropriate and standard treatment. Peking Union Medical College Hospital has achieved better curative effect in the latest 15 years than before.

Relative Effects of Age, Race, and Stage on Mortality in Gestational Choriocarcinoma.

OBJECTIVE: Gestational choriocarcinoma is a malignant form of gestational trophoblastic disease that usually arises after a molar pregnancy, but may follow any antecedent pregnancy. Investigations in this rare cancer are limited. We evaluated the prognostic effects of age, race, and stage in choriocarcinomas diagnosed for 4 decades. METHODS: Patients diagnosed as having gestational choriocarcinoma between 1973 and 2014 from the Surveillance, Epidemiology, and End Results program were eligible. Relationships with overall survival and cancer-specific survival were evaluated using log-rank testing and Cox modeling. Multivariate analyses included adjustments for age, race, and stage. RESULTS: There were 947 patients with choriocarcinoma including 403 non-Hispanic white (NHW) patients, 473 with distant stage, and 142 who died. Median age at diagnosis was 25 years for non-Hispanic black (NHB) patients and 35 years for Asian/Pacific Islanders (API) compared with 29 years for NHW patients (P = 0.0001). Five-year overall survival varied between 82% and 92% when diagnosed at the age of at least 40 years compared with less than 20 years (P < 0.0001), and from 85% to 95% in patients with distant vs local disease (P < 0.0001), respectively. Multivariate analysis demonstrated that age, race, and stage were independent predictors of mortality. Risk of death increased incrementally in patients diagnosed at 20 to 39 years of age (adjusted hazard ratio [aHR], 3.87; 95% confidence interval [CI], 1.69-8.86; P = 0.001) and at least 40 years of age (aHR, 7.18; 95% CI, 2.95-17.49; P < 0.0001) compared with 20 years or younger. Non-Hispanic black patients were the only racial group at higher risk of death compared with NHW patients (aHR, 1.86; 95% CI, 1.22-2.82; P < 0.004). Distant vs local disease added an additional risk of death (aHR, 2.43; 95% CI, 1.57-3.75; P < 0.0001) over that attributable to age at diagnosis and NHB race. Similar relationships to cancer-specific survival were also observed (P < 0.05). CONCLUSIONS: Most patients with choriocarcinoma have excellent prognosis. However, NHB patients and patients who are diagnosed at the age of at least 20 years or have distant stage have significantly worse mortality.

[Maternal deaths due to gestational trophoblastic diseases, results from the French confidential enquiry into maternal deaths, 2010-2012]. / Morts maternelles par maladies trophoblastiques gestationnelles. Résultats de l'enquête confidentielle française sur la mortalité maternelle, 2010­2012.

Gestational trophoblastic diseases (GTD) correspond to several entities which all have a common pattern: hypersecretion of human chorionic gondotrophin by trophoblastic hyperplasia. Between 2010 and 2012, there were 4 maternal deaths due to GTD (choriocarcinoma). The ratio of maternal death caused by GTD was 0,16/100,000 living births which was similar to the rate from the 2007-2009 period. These deaths represented 1.6% from the whole maternal mortality and 3.3% of the direct maternal mortality. These four deaths occurred after delivery and the diagnosis of GTD was made between 60 and 180 days in the postpartum period. Two cases seemed to be potentially avoidable. The main causes of suboptimal management were linked to delay either in diagnosis of GTD or in initiating the appropriate treatment. The analysis of these maternal deaths gave the opportunity to stress some major lessons to optimize medical management of GTD. Therefore, a patient presenting with persistent bleedings more than six weeks after delivery needs some specific exams such as plasma human chorionic gondotrophin measurement and histopathologic examination to affirm GTD and start early specific treatments generally leading to complete recovery.

An extremely rare case of postpartum gestational choriocarcinoma with long-term survival.

Gestational choriocarcinomas are highly malignant tumors with elevated serum human chorionic gonadotropin (hCG) levels. We report an extremely rare case of a 27-year-old woman who presented 4 months after normal delivery, with pulmonary, renal and intracardiac metastases of a choriocarcinoma. No primary uterine tumor was found. She was surgically treated for the renal and cardiac metastases as well as with cisplatin-etoposide chemotherapy. No recurrence has been observed 16 years after initial diagnosis, and the patient was able to have a second child. This case report shows that appropriate treatment of metastatic gestational choriocarcinoma can cure the patient without compromising her fertility.

Fertility-sparing uterine lesion resection for young women with gestational trophoblastic neoplasias: single institution experience.

PURPOSE: To evaluate the oncological safety and pregnant outcomes of fertility-sparing uterine lesion resection in treating gestational trophoblastic neoplasias. RESULTS: After the treatment of surgery and chemotherapy, all the patients achieved complete remission. With a median follow-up time of 44 months (range, 6-188), 3 patients (3.85%) relapsed within 3-26 months. Multivariate analysis showed that tumor size was the independent risk factor of recurrence and the cutoff value was 4.2cm. Among 37 patients who attempted to conceive, 31 achieved clinical pregnancy. The rate of pregnancy and live birth were 83.8% and 77.4%. Uterine rupture did not occurred no matter in cesarean section or vaginal delivery. No congenital abnormalities were reported among the live births. METHODS: From January 1995 to December 2014, 78 patients with gestational trophoblastic neoplasias who underwent fertility-sparing uterine lesion resection at Peking Union Medical College Hospital were reviewed. The complete remission rate, fertility rate, pregnant outcomes and risk factors of recurrence were analyzed. CONCLUSIONS: Fertility-sparing uterine lesion resection might be considered as a safe and reasonable alternative for high-selected young women to remove uterine lesion in the treatment of gestational trophoblastic neoplasias.

Role of Capecitabine in the Management of Gestational Trophoblastic Neoplasia: A Drug for Two Settings.

OBJECTIVE: To evaluate the role of capecitabine in the management of gestational trophoblastic neoplasia (GTN). STUDY DESIGN: The medical records of 155 patients with GTN were reviewed. All patients were treated and followed at our center. RESULTS: All patients were scored and stratified with the FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease. In the low-risk group (118 patients), 4 selected patients received capecitabine as second line of treatment, with a 75% response rate and long-term disease-free survival, and 1 of those patients needed EMA/CO to achieve cure. The cure rate was 100%. In the high-risk group 37 patients were reviewed. Capecitabine was indicated after EMA/CO or EMA/PE failure in the second, third, or sixth line. Six patients received capecitabine, with a 50% response rate, and remain as long-term survivors. Two patients who progressed with capecitabine were cured with TP/TE and EMA/PE regimens. One patient was refractory to all lines of chemotherapy. CONCLUSION: The use of capecitabine avoids multi-ple drug schemes and further toxicity for patients with curative disease, where long-term effects of therapy should be considered a second target. Its convenient oral route of administration and efficacy make capecitabine a drug to be taken into account in future studies of patients with GTN showing progression to standard regimens. Its use as new regimen in these patients must be evaluated. A greater number of cases and ideally a randomized study is needed to confirm our observation.

Maternal Near Miss According to World Health Organization Classification Among Women with a Hydatidiform Mole: Experience at the New England Trophoblastic Disease Center, 1994-2013.

OBJECTIVE: To investigate the frequency of potentially life-threatening conditions (PLTCs) and maternal near misses (MNMs) at the New England Trophoblastic Disease Center (NETDC) in recent years, when there has been earlier diagnosis of molar pregnancy. STUDY DESIGN: This study included patients with molar pregnancy at the NETDC between 1994 and 2013. Clinical and pathologic reports were reviewed. PLTC and MNM criteria and maternal deaths were searched in medical records using the World Health Organization criteria and classification. RESULTS: We identified 375 patients with molar pregnancy and no patient developed a MNM or maternal death. Only 6 (1.6%) had PLTCs (hemorrhage with hemodynamic instability, severe preeclampsia, respiratory distress, blood transfusion, and ICU admission). CONCLUSION: We observed a low rate of PLTC and no cases of MNMs or maternal deaths related to molar pregnancy, likely due to earlier diagnosis at the NETDC in recent years.

Prognosis of Patients with Gestational Trophoblastic Neoplasia and Obstetric Outcomes of Those Conceiving After Chemotherapy.

AIM: To assess prognosis of gestational trophoblastic neoplasia (GTN) and obstetric outcome after chemotherapy. PATIENTS AND METHODS: Sixty-six patients had diagnosis of hydatiform mole on curettage and 18 developed GTN. Two patients were referred with pathological diagnosis of GTN. Chemotherapy was tailored according to International Federation of Gynecology and Obstetrics risk scoring system. RESULTS: All patients with GTN but one, were recovered by chemotherapy and had no evidence of disease after a median follow-up of 80 months. Only the patient with epithelioid trophoblastic tumor died of disease. Seven out of the eight women who tried to conceive after chemotherapy became pregnant. Ten conceptions occurred, resulting in no molar pregnancy, three miscarriages and seven term-live healthy births (70.0%). All seven babies showed normal development and growth after a median follow-up of 38 months. CONCLUSION: The prognosis of women with GTN is very good, and obstetric outcomes of those who conceive after chemotherapy are similar to those of the general population.

A 10-Year Clinical Experience of Gestational Trophoblastic Disease at Rajavithi Hospital, 2001-2010.

BACKGROUND: Gestational trophoblastic disease (GTD) develops from abnormal cellular proliferation of trophoblasts following fertilization and is categorized as either an hydatidiform mole (HM) or a gestational trophoblastic neoplasia (GTN). OBJECTIVE: To analyze the clinical characteristics, incidence and treatment outcomes of GTD at Rajavithi Hospital. MATERIAL AND METHOD: Medical records of women diagnosed with GTD at Rajavithi Hospital from January 1, 2001 to December 31, 2010 were retrospectively reviewed. Disease diagnosis, treatment and follow-up data were analyzed. RESULTS: A total of 329 cases of GTD were reviewed. HM was diagnosed in 167 patients (incidence 2.32 per 1,000 deliveries); 26 patients were lost to follow-up; and 49 of the remaining 141 patients (34.8%) developed post-molar GTN. In multivariable analysis, uterus >16 week size and pre-treatment human chorionic gonadotropin (hCG) level >250,000 mIU/mL were the significant risk factors for developing post-molar GTN. Of 162 patients with GTN (incidence 2.25 per 1,000 deliveries), 15 patients were lost to follow-up, and 116 patients, 29 patients and 2 patients were classified as having low-risk GTN, high-risk GTN and placental site trophoblastic disease respectively. The overall survival rate in the low-risk group was 100% whereas in the high-risk group it was 86.2%. A modified WHO prognostic score of more than five was the significant risk factor for developing resistant GTN. CONCLUSION: GTD treatment at Rajavithi Hospital showed excellent clinical outcomes. Uterus >16 weeks size and pre- treatment hCG > 250,000 mIU/mL were the significant risk factors for developing post-molar GTN in HM patients. Classifying GTN patients into low- and high-risk groups was useful in planning treatment and counseling.

Outcomes of Metastatic Gestational Trophoblastic Neoplasia: Fourteen Year Experience from a Northern Thailand Tertiary Care Center.

Metastatic gestational trophoblastic neoplasia (GTN) is an uncommon cancer. The principal treatment consists of chemotherapy with or without surgery or radiotherapy. We here retrospectively reviewed the outcomes of metastatic GTN treated at our institute between January, 1999 and December, 2013. Sixty-three patients met the criteria. The median age was 30.0 years and almost 90% were referral cases. Nearly 40% of the studied patients presented with vaginal bleeding while 22.2% were asymptomatic. The most common antecedent pregnancy was hydatidiform mole (57.1%) followed by term pregnancy (20.6%). The median interval time from antecedent pregnancy to the development of GTN was three months and the median pretreatment B-hCG was 58,274 mIU/ ml. Stage III (74.6%) was the most common staging followed by stage IV (20.6%) and stage II (4.8%). The most frequent surgery was hysterectomy (31.7%). Thoracotomy and craniotomy were performed in three and two patients, respectively. The most common first line chemotherapy regimen was methotrexate and folinic acid (36.5%) followed by EMA (etoposide, methotrexate, actinomycin D) (34.9%), EMACO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) (17.5%) with the remission rate of 66.7%. Nearly one-third of the patients were given a subsequent chemotherapy regimen after failure with the first line therapy and showed a final response rate of 73.0%. However, in stage IV, the response to first line treatment was only 38.5%. In conclusion, the outcomes of metastatic GTN were poor especially with the higher stages.

[Results of gestational trophoblastic neoplasia treatment in the Slovak Republic in the years from 1993 to 2012]. / Výsledky liecby gestacnej trofoblastovej neoplázie v Slovenskej republike v rokoch 1993 az 2012.

OBJECTIVE: Analysis and epidemiology of gestational trophoblastic neoplasia treatment in the Slovak Republic in the years 1993-2012. DESIGN: Retrospective epidemiological national study. SETTING: Centre for gestational trophoblastic disease Ministry of Health the Slovak Republic, Bratislava. METHODS: Retrospective analysis results of gestational trophoblastic neoplasia treatment according to prognostic scoring and staging system FIGO/WHO in Centre for gestational trophoblastic disease Ministry of Health the Slovak Republic Bratislava in the years 1993-2012. RESULTS: The treatment of gestational trophoblastic neoplasia (GTN) in the Czech and Slovak Republics started in 1955 and lasted till 1993. After the split of the former Czechoslovakia the Centre for gestational trophoblastic disease was created in Slovakia. 75 patients were treated in this Centre in the years 1993-2012. According to prognostic scoring and staging system FIGO/WHO 56 (75%) patients had low-risk gestational trophoblastic neoplasia and 19 (25%) of patients had high-risk gestational trophoblastic neoplasia. There were 41 patients (55%), 2 (3%), 24 (32%) and 8 (11%) in stage I., II., III. and IV. respectively. Total curability rate was 94.7% and mortality rate was 5.3%. Curability rate 100% was achieved in stage I & II and all placental site trophoblastic tumours (PSTT), 98.3% in stage III and 50% stage IV. In the years 1993-2012 the incidence of choriocarcinoma was one in 76 273 pregnancies and one in 53 203 deliveries. The incidence of other gestational trophoblastic neoplasia in the same years was for PSTT one in 533 753 pregnancies and one in 372 422 deliveries, invasive mole one in 145 611 pregnancies and one in 101 569 deliveries, and persistent GTN one in 40 043 pregnancies and one in 27 932 deliveries. 225-241 patients were treated in the same period of time in the Czech Republic with curability rate 98.2-98. 3%. CONCLUSION: Early detection and treatment in the centre for trophoblastic disease are crucial points in the manage-ment of gestational trophoblastic neoplasia, because the effective therapy of gestational trophoblastic neoplasia with high curability rate is available.

Predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients successfully treated with methotrexate alone.

BACKGROUND: Patients with 2000 FIGO low-risk gestational trophoblastic neoplasia are commonly treated with single-agent chemotherapy. Methotrexate is widely used in this indication in Europe. Analysis of relapse after treatment and identification of factors associated with relapse would help understand their potential impacts on 2000 FIGO score evolution and chemotherapy management of gestational trophoblastic neoplasia patients. OBJECTIVE: This retrospective study analyzes the predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients whose hormone chorionic gonadotropin (hCG) normalized with methotrexate alone. STUDY DESIGN: Between 1999 and 2014, 993 patients with gestational trophoblastic neoplasia were identified in the French Trophoblastic Disease Reference Center database, of which 465 were low-risk patients whose hCG normalized with methotrexate alone. Using univariate and multivariate analysis we identified significant predictive factors for relapse after methotrexate. The Kaplan-Meier method was used to plot the outcome of patients. RESULTS: The 5-year recurrence rate of low-risk gestational trophoblastic neoplasia patients whose hCG normalized with methotrexate alone was 5.7% (confidence interval [IC], 3.86-8.46). Univariate analysis identified an antecedent pregnancy resulting in a delivery (HR = 5.96; 95% CI, 1.40-25.4, P = .016), a number of methotrexate courses superior to 5 courses (5-8 courses vs 1-4: HR = 6.19; 95% CI, 1.43-26.8, P = .015; 9 courses and more vs 1-4: HR = 6.80; 95% CI, 1.32-35.1, P = .022), and hCG normalization delay centered to the mean as predictive factors of recurrence (HR = 1.27; 95% CI, 1.09-1.49, P = .003). Multivariate analysis confirmed the type of antecedent pregnancy and the number of methotrexate courses as independent predictive factors of recurrence. A low-risk gestational trophoblastic neoplasia arising after a normal delivery had an 8.66 times higher relapse risk than that of a postmole gestational trophoblastic neoplasia (95% CI, 1.98-37.9], P = .0042). A patient who received 5-8 courses of methotrexate had a 6.7 times higher relapse risk than a patient who received 1-4 courses (95% CI, 1.54-29.2, P = .011). A patient who received 9 courses or more had an 8.1 times higher relapse risk than a patient who received 1-4 courses of methotrexate (95% CI, 1.54-42.6, P = .014). CONCLUSION: Low-risk gestational trophoblastic neoplasia following a delivery and patients who need more than 4 courses of methotrexate to normalization are at a higher risk of relapse than other low-risk patients. Allotting a higher score to the "antecedent pregnancy" FIGO item should be considered for postdelivery gestational trophoblastic neoplasia. Further analysis of the need for consolidation courses is warranted.

Mortality rate of gestational trophoblastic neoplasia with a FIGO score of ≥13.

BACKGROUND: Gestational trophoblastic diseases include premalignant (partial and complete hydatidiform moles) and malignant entities referred to as gestational trophoblastic neoplasia. Use of the International Federation of Gynecology and Obstetrics prognostic score is encouraged in cases of gestational trophoblastic neoplasia to predict the potential for the development of resistance to single-agent chemotherapy. An International Federation of Gynecology and Obstetrics score of ≥7 defines a high-risk patient and requires combination chemotherapy. Appropriate and rapid diagnosis, treatment by specialized centers, and reduction of early deaths at the time of chemotherapy initiation have led to significant improvements in survival for patients with high-risk gestational trophoblastic neoplasia. There is a crucial need for the early identification of high-risk patients with gestational trophoblastic neoplasia who have an increased death risk to organize their treatment in highly specialized centers. OBJECTIVES: The purpose of this study was to describe cases of gestational trophoblastic neoplasia that have resulted in death, particularly in a subgroup with an International Federation of Gynecology and Obstetrics prognostic score of ≥13, for whom low-dose etoposide and cisplatin induction chemotherapy recently was shown to reduce early death rate. STUDY DESIGN: We identified 974 patients from the French Center for Trophoblastic Diseases who had a diagnosis of gestational trophoblastic neoplasia from November 1999 to March 2014. Among 140 patients who were at high risk of resistance to single-agent chemotherapy (International Federation of Gynecology and Obstetrics score, ≥7), 29 patients (21%) had a score of ≥13. Mortality rate was estimated with the use of the Kaplan-Meier method. RESULTS: The 5-year overall mortality rate, after the exclusion of placental site trophoblastic tumors and epithelioid trophoblastic tumors, was 2% for patients with gestational trophoblastic neoplasia (95% confidence interval, 1.25-3.13%). High-risk patients had a 5-year mortality rate of 12% (95% confidence interval, 7.49-18.9%). Patients with an International Federation of Gynecology and Obstetrics score of ≥13 had a higher 5-year mortality rate (38.4%; 95% confidence interval, 23.4-58.6%) and accounted for 52% of the deaths in the entire cohort. Early deaths, defined as those that occur within 4 weeks after treatment initiation, occurred in 8 patients of the entire cohort. Six of them had an International Federation of Gynecology and Obstetrics score of ≥13 at presentation, of whom 5 patients had brain and/or liver metastases. CONCLUSION: Gestational trophoblastic diseases with an International Federation of Gynecology and Obstetrics score of ≥13 have an increased risk of early death. We suggest that an International Federation of Gynecology and Obstetrics score of ≥13 becomes a consensual criterion for prediction of patients with gestational trophoblastic neoplasia with increased risk of death, particularly early death. These patients justify treatment in highly specialized gestational trophoblastic disease centers and may benefit from the use of induction low-dose etoposide and cisplatin.

The influence of lung metastases on the clinical course of gestational trophoblastic neoplasia: a historical cohort study.

OBJECTIVE: To evaluate whether gestational trophoblastic neoplasia (GTN) patients with lung metastases have more adverse outcomes such as resistance to chemotherapy, recurrence or death of disease compared with patients without lung metastases. DESIGN: Historical observational cohort study. SETTING: The Netherlands. POPULATION: We identified 434 GTN patients (72 patients with lung metastases, 362 patients without metastases) between 1990 and 2012 registered in the Dutch national databases. METHODS: Baseline characteristics, recurrence rates, Methotrexate (MTX) remission rates and deaths from disease were compared between patients with lung metastases (group I) and without lung metastases (group II) using the Fisher exact test or Mann-Whitney U-test where applicable. MAIN OUTCOME MEASURES: Methotrexate resistance, recurrences and survival. RESULTS: Methotrexate resistance did not differ between group I and group II (62.9 versus 72.7% P = 0.19). However, the observed recurrence rate was significantly increased in patients with lung metastases compared with patients without metastases (16.7 versus 2.2% P < 0.0001), also after correction for antecedent pregnancy and interval (from the end of the antecedent pregnancy until the start of treatment). Disease-specific survival was 91.7% in the group with lung metastases and 100% in the patients without metastases (P < 0.0001). CONCLUSIONS: Although lung metastases are considered to be associated with a low risk of adverse outcomes, their presence appears to increase the risk for recurrence and death of disease. Further research is needed to evaluate whether the presence of lung metastases is an independent risk factor that needs adjustment in the FIGO scoring system and clinical classification system. TWEETABLE ABSTRACT: In gestational trophoblastic neoplasia (GTN) recurrence is more often observed in the case of lung metastases.