Gynecologic Oncology 143 (2016) 558–564 Contents lists available at ScienceDirect Gynecologic Oncology j ourna l homepage: www.e lsev ie r .com/ locate /ygyno Is chemotherapy necessary for patients with molar pregnancy and human chorionic gonadotropin serum levels raised but falling at 6 months after uterine evacuation? Antonio Braga a,b,c,⁎, Berenice Torres a,c, Marcelo Burlá a,b, Izildinha Maestá d, Sue Yazaki Sun e, Lawrence Lin f, José Mauro Madi g, Elza Uberti h, Maurício Viggiano i, Kevin M. Elias j, Ross S Berkowitz j a Rio de Janeiro Trophoblastic Disease Center (Maternity School of Rio de Janeiro Federal University, Antonio Pedro University Hospital of Fluminense Federal University, Maternity Ward of Santa Casa da Misericórdia do Rio de Janeiro), Rio de Janeiro, Rio de Janeiro, Brazil b Postgraduate Program in Medical Sciences, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil c Postgraduate Program in Perinatal Health, Faculty of Medicine, Maternity School of Rio de Janeiro Federal University, Brazil d Trophoblastic Diseases Center of the Clinical Hospital of Botucatu Medical School, Department of Gynecology and Obstetrics, São Paulo State University, Botucatu, São Paulo, Brazil e São Paulo Hospital Trophoblastic Disease Center, Paulista School of Medicine, São Paulo Federal University, São Paulo, São Paulo, Brazil f São Paulo Clinics Hospital Trophoblastic Disease Center, University of São Paulo, São Paulo, São Paulo, Brazil g Caxias do Sul Trophoblastic Disease Center, General Hospital of Caxias do Sul, School of Medicine, Center for Biological and Health Sciences, Caxias do Sul University, Caxias do Sul, Rio Grande do Sul, Brazil h Porto Alegre Trophoblastic Disease Center, Mario Totta Maternity Ward, Irmandade da Santa Casa de Misericórdia Hospital, Porto Alegre, Rio Grande do Sul, Brazil i Goiás Trophoblastic Disease Center, Clinical Hospital of Goiás, Goiás Federal University, Goiânia, Goiás, Brazil j NewEngland Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Reproductive Biology, Brigham andWomen's Hospital, HarvardMed- ical School, Boston, MA, USA H I G H L I G H T S • Only 0.8% of women have raised but falling hCG 6 months post molar evacuation. • More than 80% of such cases will enter remission without further therapy. • GTN treated after observation has comparable outcomes to immediate chemotherapy. ⁎ Corresponding author at: Gestational Trophoblastic D de Janeiro 22240-003, Brazil. E-mail address: bragamed@yahoo.com.br (A. Braga). http://dx.doi.org/10.1016/j.ygyno.2016.09.012 0090-8258/© 2016 Elsevier Inc. All rights reserved. a b s t r a c t a r t i c l e i n f o Article history: Received 3 July 2016 Received in revised form 6 September 2016 Accepted 10 September 2016 Objective. To compare the outcomes of Brazilian patients with molar pregnancy who continue human chori- onic gonadotropin (hCG) surveillance with those treated with chemotherapy when hCG was still positive, but falling at 6 months after uterine evacuation. Methods. Retrospective chart review of 12,526 patients with hydatidiformmole treated at one of nine Brazil- ian reference centers from January 1990 to May 2016. Results. At 6 months from uterine evacuation, 96 (0.8%) patients had hCG levels raised but falling. In 15/96 (15.6%) patients, chemotherapy was initiated immediately per FIGO 2000 criteria, while 81/96 (84.4%) patients weremanaged expectantly. Among the latter, 65/81 (80.2%) achieved spontaneous remission and 16 (19.8%) de- veloped postmolar gestational trophoblastic neoplasia (GTN). Patients who received chemotherapy following expectantmanagement requiredmore time for remission (11 versus 8months; p=0.001), had a greater interval between uterine evacuation and initiating chemotherapy (8 versus 6 months; p b 0.001), and presented with a median WHO/FIGO risk score higher than women treated according to FIGO 2000 criteria (4 versus 2, p = 0.04), but there were no significant differences in the need for multiagent treatment regimens (1/15 versus 3/ 16 patients, p = 0.60). None of the women relapsed, and no deaths occurred in either group. Conclusion. In order to avoid unnecessary exposure of women to chemotherapy, we no longer follow the FIGO 2000 recommendation to treat all patients with molar pregnancy and hCG raised but falling at 6 months after evacuation. Instead, we pursue close hormonal and radiological surveillance as the best strategy for these patients. © 2016 Elsevier Inc. All rights reserved. Keywords: Molar pregnancy Human chorionic gonadotropin Chemotherapy isease Center of Rio de Janeiro. Maternidade Escola, Universidade Federal do Rio de Janeiro, Rua Laranjeiras, 180, Laranjeiras, Rio http://crossmark.crossref.org/dialog/?doi=10.1016/j.ygyno.2016.09.012&domain=pdf http://dx.doi.org/10.1016/j.ygyno.2016.09.012 mailto:bragamed@yahoo.com.br http://dx.doi.org/10.1016/j.ygyno.2016.09.012 http://www.sciencedirect.com/science/journal/00908258 www.elsevier.com/locate/ygyno 559A. Braga et al. / Gynecologic Oncology 143 (2016) 558–564 1. Introduction Gestational trophoblastic disease (GTD) is an abnormality of preg- nancy that includes benign clinical forms (complete hydatidiform moles – CHM and partial hydatidiformmoles – PHM) with variable po- tential to develop gestational trophoblastic neoplasia (GTN), in its vari- ous spectra (invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor) [1–3]. Al- though GTD develops in 1:1000 pregnancies in North America and 1:2000 pregnancies in Europe, it is estimated to occur five to ten times more frequently in Brazil [4,5]. Serial monitoring of human chorionic gonadotropin (hCG) levels after molar uterine evacuation is essential to detectmalignant progression and initiate chemotherapy [6]. In Brazil, despite many difficulties, this postmolar follow-up is done in 38 GTD Reference Centers, spread throughout this country of continental di- mensions [7,8]. The Brazilian Reference Centers of GTD have adopted the criteria established by the International Federation of Gynecology and Obstet- rics (FIGO) for the diagnosis of postmolar GTN: rising (N10%) hCG levels for three consecutiveweeks or plateaued for fourweeks, if there is a his- tologic diagnosis of choriocarcinoma, or when the hCG level remains el- evated for 6months ormore from themolar uterine evacuation [9]. The most common reason for the diagnosis of postmolar GTN and the start of chemotherapy is a plateau or rise in hCG values [10]. However, some investigators have indicated that it is safe to maintain hormonal surveillance among patients with molar pregnancy whose hCG levels are raised but falling beyond the 6 months after uterine evacuation and that spontaneous remission will occur in most cases without che- motherapy [10–15]. While some organizations, such as the European Organisation for Treatment of Trophoblastic Diseases, argue that the presence of hCG raised but falling in the 6thmonth after molar evacuation is not an indi- cation to begin chemotherapy, there appears to be a controversy [2,16]. FIGO initially advised initiating chemotherapy when hCG was elevated but falling at 6 months after molar evacuation in 2000, retracted this opinion in 2012, but then resumed the recommendation in the FIGO Cancer Report in 2015 [9,17,18]. We must be cautious before dismissing this FIGO recommendation since postponing the chemotherapy in these patients with molar preg- nancy and hCG levels present over 6 months after uterine evacuation could worsen the prognosis of the GTN, due to the potential develop- ment of tumor mutations and consequent chemoresistance (an impor- tant cause of mortality among Brazilian women with GTN) [4]. Furthermore, delay could increase the FIGO risk score for these patients as the “interval between antecedent pregnancy and start of chemother- apy” is included in the current FIGO/WHO Prognostic Scoring System, which would mean higher risk scores and potentially more treatment withmultiagent regimens for patients due to delayed initiation of treat- ment [19–22]. The present study was undertaken to compare the outcomes of Bra- zilian patients with molar pregnancy that continued hCG surveillance with those treated with chemotherapy when hCG was still positive, but falling at 6 months after uterine evacuation. We also wanted to identify risk factors that were associated with the development of GTN in patientswho continued hCGmonitoring. The studywas initiated to advance our understanding if it was prudent to continue hCG moni- toring versus initiating chemotherapy in patients with elevated but fall- ing hCG levels 6 months after molar evacuation. 2. Material and methods 2.1. Study design This is a retrospective cohort study of patientswithmolar pregnancy followed at one of nine Brazilian GTD Reference Centers: in Rio de Janeiro (Maternity School of Rio de Janeiro Federal University, Antonio Pedro University Hospital of Fluminense Federal University, Maternity Ward of Santa Casa da Misericórdia do Rio de Janeiro – data entered by AB and audited byMB), in Goiânia (Clinical Hospital of Goiás Federal University – data entered by MV and audited by MB), in Porto Alegre (Mario Totta Maternity Ward at Irmandade da Santa Casa de Misericórdia Hospital – data entered by EU and audited byMB), in Caxi- as do Sul (General Hospital of Caxias do Sul – data entered by JMM and audited by MB), in São Paulo (São Paulo Hospital of São Paulo Federal University and São Paulo Clinics Hospital of University of São Paulo – data entered by SYS and LL and audited byMB) and in Botucatu (Clinical Hospital of São Paulo State University – data entered by IM and audited by MB) from January 1990 to May 2016. 2.2. Study participants Molar pregnancy was suspected when women presented with symptoms of pregnancy or vaginal bleeding combinedwith an elevated hCG level. The diagnosis of molar pregnancy in all cases was strength- ened by sonographic evaluation of the uterus. All patients had uterine evacuation performed using suction curettage with histopathological confirmation of CHM or PHM. This study includes all patients treated at one of the above centers during the study period, who adhered to the postmolar follow-up and presented with hCG levels raised but falling at 6 months after uterine evacuation, and whose medical records were complete and available for review. The following patients were excluded: those with non- molar pregnancy; who had hysterectomy to treat molar pregnancy (12 patients); those who became pregnant during the postmolar fol- low-up (148 patients) or were lost to postmolar follow-up (178 pa- tients); with histological diagnosis of choriocarcinoma (98 patients), placental site trophoblastic tumor (26 patients) or epithelioid tropho- blastic tumor (9 patients); andwomen later found to have false-positive or (“phantom”) hCG (36 patients). 2.3. Postmolar follow-up Postmolar follow-up, in addition to contraception as suggested and provided to patients, consisted of clinical examinations and laboratory tests, including the measurement of hCG levels until gonadotropin remission. Remission was defined as three consecutive weekly results of hCG values below 5 IU/L. After that, medical visits and measurement of hCG levels continued monthly for six months in the case of spontaneous remission. After chemotherapy, all the patients underwent follow-up for at least a year with monthly hCG surveillance after the first normal hCG value was obtained. When patients did not attend the scheduled visits, a social worker and hospital psychologist actively tried to contact them by phone and telegram to identify what was hindering compliance and to motivate them to return to follow-up. The patients with molar pregnancy with hCG levels raised but falling at 6 months after uterine evacuation and not immediately treated with chemotherapy were strictly followed with weekly hCG measurement and monthly chest radiograph and Doppler ultrasound scan of the pelvis in order to detect invasive mole or early metastasis. Until the year 2000, all patients were systemati- cally treated with chemotherapy in these cases. After that, the adoption of expectant management or immediate treatment of these patients was made after medical discussion, informed con- sent and individualization of the case. No formal randomization was used. Measurement in all nine Reference Centers employed the Sie- mens Diagnostic Products Corporation (DPC) Immulite® assay. The reference value for normal results was an hCG value below 5 IU/L. 560 A. Braga et al. / Gynecologic Oncology 143 (2016) 558–564 2.4. Diagnosis, staging, risk factors and treatment of gestational trophoblas- tic neoplasia Malignant progressionwas diagnosed using the criterion established by FIGO 2000 [9]. Lungmetastaseswere detected using a chest X-ray, al- though computed tomography scan was also sometimes used as an aid in follow-up and treatment [9]. Nuclear magnetic resonance imaging of the brain and abdomen was used for patients where pulmonary lesions were detected. GTN was staged according to the FIGO 2000 criteria: I – disease confined to the uterus; II – disease extends to the outside of the uterus, but is limited to the genital structures; III – disease extends to the lungs, with or without genital tract involvement; and IV – all other metastatic sites. Prognostic scoring for resistance to chemotherapy followed the FIGO/WHO Prognostic Scoring System [9]. Methotrexate and folinic acid rescue (MTX/FA) 1mg/kg intramuscu- lar and 0.1 mg/kg per oral, respectively, was used as a first line treat- ment in all cases of low-risk GTN. In cases of chemoresistance, second line chemotherapy was performed with actinomycin-D (Act-D) 1.25 mg intravenous pulse every 15 days. The third line chemotherapy treatment used was the EMA/CO regimen (etoposide, MTX/FA, Act-D, cyclophosphamide, and vincristine). 2.5. Outcomes The primary outcome was the occurrence of GTN among the study population. Secondary outcomes included the occurrence ofmetastases, the presence of high risk FIGO score, the need ofmultiagent chemother- apy, time to eventual remission, and occurrence of death. 2.6. Variables Collected patient variables included the patient age (years), hCG level preevacuation (IU/L), the gestational age at diagnosis based on date of last menstruation (weeks), the histology of molar pregnancy (CHM or PHM), hCG level at 6 months after molar evacuation (IU/L), and the time to hCG level normalization (months). Among cases of GTN, selected variables included the time interval between the uterine evacuation and the beginning of chemotherapy (months), the presence of metastasis, the presence of high risk FIGO score, the treatment with multiagent chemotherapy, the number of chemotherapy cycles, and the occurrence of death. 2.7. Statistical analysis Normality among continuous variables was tested using the D'Agostino-Pearson omnibus test. Normally distributed data were ana- lyzed using a Student's t-test, while non-normally distributed datawere analyzed using the Mann-Whitney U test. The Chi-square and Fisher's exact testswere used to compare proportions. The alpha level for signif- icance for all testswas set at 0.05. InStat GraphPad software was used to perform statistical analyses (GraphPad InStat version 6.0, GraphPad Software, San Diego, CA). 2.8. IRB approval This study was approved by the local Institutional Review Board of the Maternity School of the Federal University of Rio de Janeiro, associ- ated with the Brazilian Research Ethics Committee, under protocol number 572,887 (CAAE 23129813.0.1001.5275). 3. Results Fig. 1 represents a flow diagram describing the study population. From January 1990 to May 2016, 12,526 patients were treated at the participating Reference Centers for molar pregnancy. Among these, 8899 (71%) achieved hCG remission spontaneously within 6 months of uterine evacuation, 3531 (28.2%) developed postmolar GTN and 96 (0.8%) patients had hCG levels raised but falling 6 months after uterine evacuation and were included in our study. Considering only patients with hCG levels elevated at 6months after uterine evacuation, we observed that 15 (15.6%) patients were treated with chemotherapy based on the FIGO 2000 criteria, and 81 (84.4%) pa- tients were followed with expectant management. Among the 81 pa- tients who were followed, 65 (80.2%) patients achieved spontaneous remission, and 16 (19.8%) developed late postmolar GTN (due to pla- teau or rising hCG levels). None of the women relapsed, and no deaths have occurred. Table 1 summarizes the characteristics of Brazilian women with raised but falling human chorionic gonadotropin serum levels at 6 months after uterine evacuation not treated with chemotherapy, de- spite the FIGO 2000 criteria. Median age (29 versus 25 years old; p = 0.11) and median gestational age at diagnosis (10 versus 12 weeks; p = 0.13) among women in this group achieving spontaneous remis- sion and progressing to GTN were similar. However, when compared to women who later went on to develop GTN, those women who achieved spontaneous remission had median lower pre-evacuation hCG levels (100,000 versus 225,000 IU/L; p = 0.02) and median lower hCG levels at 6 months after uterine evacuation (68 versus 546 IU/L; p = 0.02, also shown in Fig. 2). There was also a trend towards a lower prevalence of the histologic diagnosis of CHM (67.7 versus 93.8%; p = 0.06), although this did not reach statistical significance. No deaths were reported. The characteristics of all women from the study population treated with chemotherapy, whether at 6 months following uterine evacuation or later due to a plateau or rising hCG, are summarized in Table 2 and Fig. 3. Patients that received chemotherapy due to FIGO 2000 criteria were older than those treated due to late progression GTN (32 versus 25 years old; p = 0.01). There were no differences between these groups, in terms of themedian preevacuation hCG level (219,651 versus 225,000 IU/L; p=0.51), median gestational age at diagnosis (12 versus 12 weeks of gestation; p=0.96), the histologic diagnosis of CHM (86.6 versus 93.8%; p=0.60), median hCG level at 6 months after evacuation (190 versus 546 IU/L; p = 0.26), occurrence of metastasis (13.3 versus 12.5%; p = 1.0), or duration of follow up (24 versus 36 months; p = 0.56). Patients with a diagnosis of late GTN, when compared with those treated due to FIGO 2000 criteria, did require more time for hCG level normalization (11 versus 8 months; p= 0.001) and had a greater interval between uterine evacuation and beginning of chemotherapy (8 versus 6 months; p b 0.001). Consequently, the medianWHO/FIGO risk score was higher among women receiving chemotherapy for late pro- gression to GTN (4 versus 2, p=0.04), but therewere no significant dif- ferences either in the total number of chemotherapy cycles (single agent: 4 (4–8) versus 3 (3–7); p = 0.48 and multiagent regimen: 5 (4–8) versus 4 (4); p=0.51) or the need for multiagent treatment reg- imens (3/16 patients versus 1/15, p=0.60) to achieve remission. There were no reported cases of relapsed GTN or death. 4. Discussion We have shown that it appears to be safe to follow patients with molar pregnancy and hCG serum levels raised but falling at 6 months after uterine evacuation, with 80.2% of these patients achieving hor- monal remission in a median of 8 months. Our observation is similar to others, but is in contrast to FIGO criteria that recommend the begin- ning of chemotherapy treatment for these patients [9–15]. We would like to highlight that our data come from a region where no similar work has been previously reported. Agarwal et al. identified retrospectively 75/13,910 (0.5%) patients withmolar pregnancy treated at Charing Cross Hospital with persistent but falling hCG at 6 months after uterine evacuation [10]. Among 66 patients with hormonal surveillance, 65 (98%) went to spontaneous remission. Similar to our results, they found higher median hCG levels at 6 months after 12,526 patients with molar pregnancy 8,899 (71%) patients with spontaneous remission 3,531 (28.2%) patients with progression to GTN 96 (0.8%) patients with hCG raised but falling 6 months after uterine evacuation 15 (15.6%) patients with chemotherapy due FIGO 2000 criteria 81 (84.4%) patients were followed with expectant management 13 patients Stage I (11/13 low risk; 2/13 high risk) 8/13 MTX/FA 3/13 Act-D (after MTX/FA chemoresistance) 2/13 Act-D (as initial treatment, due to nonmetastatic high risk GTN) 2 patients Stage III (1/2 low risk; 1/2 high risk) 1/2 Act-D (after MTX/FA chemoresistance) 1/2 EMA/CO (as initial treatment, due to high risk GTN) No relapses or deaths 16 (19.8%) patients treated with chemotherapy due to plateau or rising hCG 65 (80.2%) patients spontaneously achieved remission 14 patients Stage I (14/14 low risk) 11/14 MTX/FA 2/14 Act-D (after MTX/FA chemoresistance) 1/14 EMA/CO (after MTX/FA and Act-D chemoresistance) 2 patients Stage III (1/2 low risk; 1/2 high risk) 1/2 EMA/CO (after MTX/FA and Act-D chemoresistance) 1/2 EMA/CO (as initial treatment, due to high risk GTN) No relapses or deaths Fig. 1. Flow diagram summarizing the derivation of the study population. 561A. Braga et al. / Gynecologic Oncology 143 (2016) 558–564 evacuation in those womenwho developed late GTN (13 IU/L, range 5– 887 versus 157 IU/L, range 6–6438; p = 0.004). However, all patients attained remission, and they did not report any relapse of GTN. Recently, new data from the United Kingdom Trophoblastic supra-regional dis- ease treatment centers atWeston Park Hospital (Sheffield) and Charing Cross Hospital (London) reported 35/16,779 (0.2%) women with molar pregnancy and raised but falling serumhCG levels followedwith contin- ued surveillance 6 months after evacuation [15]. The authors observed hormonal remission in 30 of the patients (86%) spontaneously, similar to our results (80.2%); one woman was lost to follow up prior to hCG normalization (3%) and the remaining four women (11%) were treated Table 1 The characteristics of Brazilian women with molar pregnancy not treated with chemotherapy levels at 6 months after uterine evacuation. Variable Outcome after ob Spontaneous rem Age, years; median (range) 29 (14–47) hCG preevacuation level, IU/L; median (range) 100,000 (800–90 Gestational age at diagnosis, weeks, median (range) 10 (4–28) Histology of molar pregnancy Complete hydatidiform mole, n (%) 44 (67.7%) Partial hydatidiform mole, n (%) 21 (32.3%) hCG level 6 months after evacuation, IU/L; median (range) 68 (6–1750) Time to hCG level normalization, months; median (range) 8 (6–36) Duration of follow up, months; median (range) 14 (9–46) Occurrence of relapse or death, n (%) 0 (0) GTN – gestational trophoblastic neoplasia. hCG – human chorionic gonadotropin. with chemotherapy due to late GTN. Nowoman developed relapsed dis- ease and overall survival was 100%. Our investigation reinforces previous findings in the literature showing that the occurrence of hCG levels raised but falling at 6months after uterine evacuation is extremely low, affecting b1% of patients with molar pregnancy. In such cases, it appears to be safe to maintain hor- monal and radiological surveillance, since approximately 80% of pa- tients will normalize the levels of hCG spontaneously [10–15]. However, the current study also adds some new findings. Among pa- tients not treated with chemotherapy, despite FIGO 2000 criteria, with raised but falling hCG serum levels at 6months after uterine evacuation, , despite FIGO 2000 criteria, with raised but falling human chorionic gonadotropin serum servation at 6 months post-evacuation p-Value ission N = 65 (80.2%) Late progression to GTN N = 16 patients (19.8%) 25 (14–49) 0.11 0,000) 225,000 (1800–567,340) 0.02 12 (6–23) 0.13 15 (93.8%) 0.061 (6.2%) 546 (7–3258) 0.02 11 (7–26) 0.002 36 (14–67) b0.001 0 (0) – Fig. 2. Human chorionic gonadotropin levels raised but falling among Brazilian women with molar pregnancy at 6 months after uterine evacuation, not treated with chemotherapy, despite FIGO 2000 criteria. 562 A. Braga et al. / Gynecologic Oncology 143 (2016) 558–564 the histology of CHM and higher hCG level preevacuation at 6 months from evacuation were associated with an increased risk of developing late GTN. Patients who were followed with hormonal surveillance and developed late GTNweremore likely to have a higherWHO/FIGO prog- nostic risk score, mostly due to the increased time between evacuation and chemotherapy. Interestingly, however, this delay did not worsen the GTN extent of disease or the response to treatment and did not in- crease the need for a multiagent regimen. Our study does have some important limitations. Data were collect- ed from different hospital databases and may not reflect the Brazilian general population. As referral centers, these data may overestimate the true prevalence of GTN in the general population. A commercial kit designed to diagnose pregnancy was used to measure hCG levels, and not to discriminate all its fractions. Despite investigating a large se- ries of patients with molar pregnancy, the low incidence of cases of Table 2 Comparison of Brazilian women with molar pregnancy treated with chemotherapy, either due months after uterine evacuation) or later due to progression to GTN. Variable Indicatio Due to FI Age, years; median (range) 32 (17–4 hCG preevacuation level, IU/L; median (range) 219,651 ( Gestational age at diagnosis, weeks, median (range) 12 (9–16 Histology of molar pregnancy Complete hydatidiform mole 13/15 (86 Partial hydatidiform mole 2/15 (13. hCG level 6 months after evacuation, IU/L; median (range) 190 (37– Time to hCG level normalization, months; median (range) 8 (7–10) Time between evacuation and chemotherapy, months; median (range) 6 (6–8) hCG level pre-treatment, IU/L; median (range) 240 (42– Occurrence of metastasis No, n (%) 13 (86.7% Yes, n (%) 2 (13.3%) WHO/FIGO Prognostic Risk Score 2 (1–9) Low risk, n (%) 12 (80%) High risk, n (%) 3 (20%) Treatment Single agent, n (%) 14 (93.3% Multiagent regimen, n (%) 1 (6.7%) Number of chemotherapy cycles necessary to GTN remission Single agent, median (range) 3 (3–7) Multiagent regimen, median (range) 4 (4) Duration of follow up, months; median (range) 24 (12–8 Occurrence of relapse or death, n 0 (0) GTN – gestational trophoblastic neoplasia. hCG – human chorionic gonadotropin. WHO/FIGO – World Health Organization/International Federation of Gynecology and Obstetric patients with raised but falling hCG serum levels at 6months after uter- ine evacuation is a bias that should be considered. In conclusion, in settings where patients with molar pregnancy can be closely followedwith hormonal and radiological surveillance, we be- lieve it is appropriate to adopt the strategy to “watch andwait”, because the hCG levels in the vast majority of women will decrease to normal [11]. These cases should be evaluated in GTD reference centers and must be discussed individually within specialized teams to decide with the patient and her family on the best therapeutic strategy. Contin- ued surveillance avoids exposing women unnecessarily to the potential toxicities of chemotherapy [10,21,22]. In our series, we should empha- size that expectant management spared 80% of patient’s unnecessary chemotherapy and its side effects, although methotrexate and actino- mycin-D are generally well tolerated. Moreover, patients, who were monitored with hCG surveillance and developed late GTN, had no in- creased risk formetastatic disease and no increased need formultiagent chemotherapy. Therefore, when patientswithmolar pregnancy have el- evated but falling hCG levels at 6 months after evacuation, we believe it is most reasonable to continue hCG follow up and not initiate immedi- ate chemotherapy treatment. Conflict of interests The authors declare no conflict of interests. Funding This research was supported by the Carlos Chagas Filho Foundation for Research Support in the State of Rio de Janeiro/Brazil (FAPERJ) – an agency under the Brazilian Ministry of Science and Technology (AB); and the Donald P. Goldstein MD Trophoblastic Tumor Registry Endow- ment (KME, RSB) and the Dyett Family Trophoblastic Disease Research and Registry Endowment (KME, RSB). The funding agencies had no di- rect role in the generation of the data or manuscript. to FIGO 2000 criteria (human chorionic gonadotropin serum levels raised but falling at 6 n for chemotherapy p-Value GO 2000 criteria N = 15 patients Due to late GTN N = 16 patients 9) 25 (14–49) 0.01 73,444–745,000) 225,000 (1800–567,340) 0.51 ) 12 (6–23) 0.96 .6%) 15/16 (93.8%) 0.60 4%) 1/16 (6.2%) 1130) 546 (7–3258) 0.26 11 (7–26) 0.001 8 (6–10) b0.001 1890) 610 (21–3890) 0.30 ) 14 (87.5%) 1.0 2 (12.5%) 4 (2−13) 0.04 15 (93.8%) 0.33 1 (6.2%) ) 13 (81.3%) 0.60 3 (18.7%) 4 (4–8) 0.48 5 (4–8) 0.51 4) 36 (14–67) 0.56 0 (0) – s. 16 patients treated with chemotherapy due to plateau or rising hCG after being followed with expectant management Low Risk N = 15 High Risk N = 1 EMA/CO N=1 4 cycles Remission N=2 Median 4 cycles (3-5) Remission N=11 Median 4 cycles (4-8) MTX/FAResistant Act-DResistant Remission N=2 Median 5 cycles (4-8) EMA/CO 15 patients immediately treated with chemotherapy by FIGO 2000 criteria for hCG raised but falling at 6 months after uterine evacuation Low Risk N = 12 High Risk N = 3 EMA/CO N=1 4 cycles Act-D N=2 Median 4 cycles (3-5) Remission N=4 Median 4 cycles (3-5) Remission N=8 Median 3 cycles (3-7) MTX/FAResistant Act-D Treatment according to FIGO 2000 Criteria Treatment after Expectant Management Fig. 3. 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Introduction 2. Material and methods 2.1. Study design 2.2. Study participants 2.3. Postmolar follow-up 2.4. Diagnosis, staging, risk factors and treatment of gestational trophoblastic neoplasia 2.5. Outcomes 2.6. Variables 2.7. Statistical analysis 2.8. IRB approval 3. Results 4. Discussion Conflict of interests Funding References