Immunotherapy in the treatment of chemoresistant gestational trophoblastic neoplasia - systematic review with a presentation of the first 4 Brazilian cases.

OBJECTIVE: To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment. METHODS: Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board. RESULTS: Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab. CONCLUSION: Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.

The impact of the distance traveled between residence and gestational trophoblastic neoplasia reference center and clinical outcomes in Brazilian women.

OBJECTIVE: To relate the distance traveled from the patient's residence to the gestational trophoblastic neoplasia (GTN) reference center (RC) and the occurrence of unfavorable clinical outcomes, as well as to estimate the possible association between this distance and the risk of metastatic disease at presentation, the need for multiagent chemotherapy to achieve remission and loss to follow-up before remission. STUDY DESIGN: Retrospective historical cohort study of patients with GTN followed at 8 Brazilian GTN-RC, from January 1st, 2000 - December 31st, 2017. RESULTS: Evaluating 1055 cases of GTN, and using a receiver operating characteristic curve, we found a distance of 56 km (km) from the residence to the GTN-RC (sensitivity = 0.57, specificity = 0.61) best predicted the occurrence of at least one of the following outcomes: occurrence of metastatic disease, need for multiagent chemotherapy to achieve remission, or loss to follow-up during chemotherapy. Multivariate logistic regression adjusted by age, ethnicity, marital status and the reference center location showed that when the distance between residence and GTN-RC was ≥56 km, there was an increase in the occurrence of metastatic disease (relative risk - RR:3.27; 95%CI:2.20-4.85), need for multiagent chemotherapy (RR:1.36; 95%CI:1.05-1.76), loss to follow-up during chemotherapy (RR:4.52; 95CI:1.93-10.63), occurrence of chemoresistance (RR:4.61; 95%CI:3.07-6.93), relapse (RR:10.27; 95%CI:3.08-34.28) and death due to GTN (RR:3.62; 95%CI:1.51-8.67). CONCLUSIONS: The distance between the patient's residence and the GTN-RC is a risk factor for unfavorable outcomes, including death from this disease. It is crucial to guarantee these patients get prompt access to the GTN-RC and receive follow-up support.

Presentation, medical complications and development of gestational trophoblastic neoplasia of hydatidiform mole after intracytoplasmic sperm injection as compared to hydatidiform mole after spontaneous conception - a retrospective cohort study and literature review.

OBJECTIVE: To describe the natural history of hydatidiform mole (HM) after intracytoplasmic sperm injection (ICSI), emphasizing the clinical and oncological outcomes, as compared to patients who had HM after spontaneous conception (SC). STUDY DESIGN: Retrospective historical cohort study of patients with HM followed at the Rio de Janeiro Federal University, from January 1st 2000-December 31st 2020. RESULTS: Comparing singleton HM after SC to those following ICSI there were differences in terms of maternal age (24 vs 34 years, p < 0.01), gestational age at diagnosis (10 vs 7 weeks, p < 0.01), preevacuation human chorionic gonadotropin levels (200,000 vs 99,000 IU/L, p < 0.01), occurrence of genital bleeding (60.5 vs 26.9%, p < 0.01) and hyperemesis (23 vs 3.9%, p = 0.02) at presentation, and time to remission (12 vs 5 weeks, p < 0.01), respectively. There were no differences observed in the cases of twin mole, regardless of the form of fertilization that gave rise to HM, except molar histology with greater occurrence of partial hydatidiform mole (10.7 vs 40.0%, p = 0.01) following ICSI. Univariate logistic regression for occurrence of postmolar GTN after ICSI identified no predictor variable for this outcome. However, after adjusting for maternal age and complete hydatidiform mole histology, multivariable logistic regression showed the risk of GTN with HM after ICSI had an adjusted odds ratio of 0.22 (95%CI:0.05-0.93, p = 0.04), suggesting a possible protective effect when compared to HM after SC. CONCLUSIONS: Singleton HM after ICSI are diagnosed earlier in gestation, present with fewer medical complications, and may be less likely to develop GTN when compared with HM after SC.

Influence of COVID-19 pandemic on molar pregnancy and postmolar gestational trophoblastic neoplasia: An observational study.

OBJECTIVE: To assess whether the incidence and aggressiveness of molar pregnancy (MP) and postmolar gestational trophoblastic neoplasia (GTN) changed during the COVID-19 pandemic. DESIGN: Observational study with two separate designs: retrospective multicentre cohort of patients with MP/postmolar GTN and a cross-sectional analysis, with application of a questionnaire. SETTING: Six Brazilian Reference Centres on gestational trophoblastic disease. POPULATION: 2662 patients with MP/postmolar GTN treated from March-December/2015-2020 were retrospectively evaluated and 528 of these patients answered a questionnaire. METHODS: Longitudinal retrospective multicentre study of patients diagnosed with MP/ postmolar GTN at presentation and a cross-sectional analysis, with application of a questionnaire, exclusive to patients treated during the period of study, to assess living and health conditions during the COVID-19 pandemic compared with previous years. MAIN OUTCOME MEASURES: The incidence of MP/postmolar GTN. RESULTS: Compared with the last 5 pre-pandemic years, MP/postmolar GTN incidence remained stable during 2020 (COVID-19 pandemic). Multivariable logistic regression, adjusted for the patient age, showed that during 2020, presentation with MP was more likely to be >10 weeks of gestation (adjusted odds ratio [aOR] 2.50, 95% confidence interval [CI] 1.90-3.29, P < 0.001), have a pre-evacuation hCG level ≥100 000 iu/l (aOR 1.77, 95% CI 1.38-2.28, P < 0.001) and time to the initiation of chemotherapy ≥7 months (aOR 1.86, 95% CI 1.01-3.43, P = 0.047) when compared with 2015-2019. CONCLUSIONS: Although the incidence of MP/postmolar GTN remained stable during the COVID-19 pandemic in Brazil, the pandemic was associated with greater gestational age at MP diagnosis and more protracted delays in initiation of chemotherapy for postmolar GTN.

Folinic acid rescue during methotrexate treatment for low-risk gestational trophoblastic neoplasia - How much is just right?

OBJECTIVE: To compare the outcomes of patients with low-risk gestational trophoblastic neoplasia (GTN) treated with 8-day methotrexate (MTX) with two different regimens of folinic acid (FA). METHODS: Retrospective cohort study of low-risk GTN followed at Rio de Janeiro Federal University, from January/2000-December/2019 with 8-day MTX with FA at 0.1 mg/kg versus 15 mg fixed dose. RESULTS: Among 667 patients with low-risk GTN, 323 were treated with FA at 0.1 mg/kg and 142 with FA at 15 mg fixed dose. The weight-based and fixed dose groups were comparable in terms of clinical profile but did differ in the hCG pretreatment level (8883 versus 5127 IU/L, p < 0.01) and FIGO risk score 5/6 (3.4% versus 18.3%, p < 0.01), respectively. Despite this, there was no difference in the remission rate in first-line treatment (76.8 versus 81%, p = 0.33), although FA at 0.1 mg/kg had a significantly higher number of chemotherapy cycles to remission (5 versus 4, p < 0.01), need to delay chemotherapy due to toxicity (6.8 versus 2.8%, p < 0.01) and time to remission, (12 versus 8 weeks, p < 0.01), respectively. A logistic regression analysis showed that the different FA rescue regimens appeared comparable in terms of achieving remission in first-line chemotherapy for low-risk GTN (OR:5.16, CI95%:0.84-31.64, p = 0.08). CONCLUSION: FA with 15 mg fixed dose as compared to 0.1 mg/kg of FA was associated with similar primary remission rate, relapse or death among low-risk GTN treated with 8-day MTX. This regimen is highly practical, reduces visits to health facilities, appears equally safe and may be preferable with the 8-day MTX regimen in the treatment of low-risk GTN.

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.

Comparison of treatment for low-risk GTN with standard 8-day MTX/FA regimen versus modified MTX/FA regimen without chemotherapy on the weekend.

OBJECTIVE: To compare the outcomes of patients with low-risk gestational trophoblastic neoplasia (GTN) treated with standard 8-day methotrexate/folinic acid (MTX/FA) versus modified regimen. METHODS: Retrospective cohort study of patients with low-risk GTN followed at Rio de Janeiro Federal University, from January/1990-December/2017 with standard 8-day MTX/FA or modified regimen (MTX administered on the 8th day rather than 7th) to avoid treatment on the weekend. RESULTS: From 937 patients with low-risk GTN, 538 were treated with standard MTX/FA and 98 patients received modified regimen. Both groups were comparable in age (p = .749), antecedent pregnancy (p = .221), time to initiate chemotherapy (p = .926), hCG pretreatment level (p = .112) and WHO/FIGO prognostic risk score (p = .723). Patients treated with modified MTX/FA had twice of cases of metastatic lung disease compared with the standard regimen (22.5% vs 10.6%; p = .002). The rate of remission (p = .999), number of cycles to remission in the first-line (p = .966), chemoresistance (p = .500), time to switch to second-line therapy (p = .176), need for multiagent chemotherapy (p = .084), relapse (p = .122) or death (p = .475) was the same for both MTX/FA regimen. However, although patients receiving modified MTX/FA required a higher total number of remission cycles (6 vs 5 cycles; p = .004) and longer time to remission (19 vs 16 weeks; p < .001) when compared with the standard regimen, these variables showed no significant differences after multivariate logistic regression adjusted for lung metastasis. CONCLUSION: The modified 8-day MTX/FA regimen didn't compromise oncologic outcomes for women with low-risk GTN. This regimen appears to be an acceptable alternative to standard 8-day MTX/FA when treatment on weekend isn't an option.

Can carboplatin or etoposide replace actinomycin-d for second-line treatment of methotrexate resistant low-risk gestational trophoblastic neoplasia?

OBJECTIVE: To evaluate the impact of periodic shortage of actinomycin-d (Act-d) in the treatment of Brazilian patients with low-risk gestational trophoblastic neoplasia (GTN) after methotrexate and folinic acid rescue (MTX/FA) resistance, treated alternately with carboplatin or etoposide as a second-line regimen. METHODS: Retrospective cohort that included patients with failure of first-line MTX/FA regimen for low-risk GTN treated at Rio de Janeiro Federal University, Universidade Federal de São Paulo and Irmandade da Santa Casa de Misericórdia de Porto Alegre, from January/2010- December/2017. RESULTS: From 356 patients with low-risk GTN treated with MTX/FA, 75 (21.1%) developed resistance, of which 40 (53.3%) received Act-d, 23 (30.7%) carboplatin and 7 (9.3%) etoposide. Although patients treated with single-agent chemotherapy as a second-line regimen had comparable clinical and primary treatment characteristics, those treated with Act-d (80%, p = 0.033) or etoposide (71.4%, p = 0.025) had higher remission rates when compared with carboplatin (47.8%). Only 29% of patients treated with carboplatin received the chemotherapy cycles without delay compared to Act-d (98%, p < 0.001) or etoposide (85%, p = 0.009). Patients treated with carboplatin had significantly more hematological toxicity, notably anemia (30.4%, p = 0.008), lymphopenia (47.7%, p < 0.001) and thrombocytopenia (43.4%, p < 0.001), as well as a higher occurrence of febrile neutropenia (14.4%, p = 0.044) and vomiting (60%, p < 0.001) than those receiving Act-d (5%, none, 2.5%, none, 10%, respectively). CONCLUSION: Carboplatin did not have a satisfactory clinical response rate, likely due to severe hematological toxicity, which postponed chemotherapy. Our results reinforce the preference for Act-d as a second-line agent in patients with low-risk GTN after MTX/FA resistance.

Is chemotherapy always necessary for patients with nonmetastatic gestational trophoblastic neoplasia with histopathological diagnosis of choriocarcinoma?

OBJECTIVE: To evaluate expectant management versus immediate chemotherapy following pathological diagnosis of gestational choriocarcinoma (GCC) in patients with nonmetastatic disease. METHODS: Multicenter retrospective cohort that included patients with histological diagnosis of GCC with nonmetastatic disease followed at one of thirteen Brazilian referral centers for gestational trophoblastic disease from January 2000 to December 2016. RESULTS: Among 3191 patients with gestational trophoblastic neoplasia, 199 patients with nonmetastatic GCC were identified. Chemotherapy was initiated immediately in 152 (76.4%) patients per FIGO 2000 guideline, while 47 (23.6%) were managed expectantly. Both groups presented with similar characteristics and outcomes. All patients (n=12) who had normal human chorionic gonadotropin (hCG) in the first 2-3weeks of expectant management achieved complete sustained remission with no chemotherapy. Only 44.7% (21 patients) of patients who were expectantly managed needed to receive chemotherapy due to plateauing or rising hCG level in the first 2-3weeks of follow up. The outcome of patients receiving chemotherapy after initial expectant management was similar to those who received chemotherapy immediately after the diagnosis in terms of need for multi-agent chemotherapy or number of cycles of chemotherapy. There was no case of relapse or death in either group. Logistic regression analysis showed that age≥40years and hCG≥92,428IU/L at GCC diagnosis were risk factors for needing chemotherapy after initial expectant management of nonmetastatic GCC. CONCLUSION: In order to avoid exposing patients unnecessarily to chemotherapy, close surveillance of women with pathological diagnosis of nonmetastatic GCC seems to be a safe practice, particularly for those who have a normal hCG at the time of diagnosis. If confirmed by other studies, the FIGO guidelines may need to be revised.

Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after controlling for risk factors?

OBJECTIVE: To evaluate the influence of hormonal contraception (HC) on the development and clinical aggressiveness of gestational trophoblastic neoplasia (GTN) and the time for normalization of human chorionic gonadotropin (hCG) levels. METHODS: A retrospective cohort study was conducted with women diagnosed with molar pregnancy, followed at the Rio de Janeiro Trophoblastic Disease Center, between January 2005 and January 2015. The occurrence of postmolar GTN and the time for hCG normalization between users of HC or barrier methods (BM) during the postmolar follow-up or GTN treatment were evaluated. RESULTS: Among 2828 patients included in this study, 2680 (95%) used HC and 148 (5%) used BM. The use of HC did not significantly influence the occurrence of GTN (ORa: 0.66, 95% CI: 0.24-1.12, p=0.060), despite different formulations: progesterone-only (ORa: 0.54, 95% CI: 0.29-1.01, p=0.060) or combined oral contraception (COC) (ORa: 0.50, 95% CI: 0.27-1.01, p=0.60) or with different dosages of ethinyl estradiol: 15mcg (ORa, 1.33, 95% CI 0.79-2.24, p=0.288), 20mcg (ORa: 1.02, 95% CI: 0.64-1.65, p=0.901), 30mcg (ORa: 1.17, 95% CI: 0.78-1.75, p=0.437) or 35mcg (ORa: 0.77, 95% CI: 0.42-1.39, p=0.386). Time to hCG normalization ≥10weeks (ORa: 0.58, 95% CI: 0.43-1.08, p=0.071) or time to remission with chemotherapy≥14weeks (ORa: 0.60, 95% CI: 0.43-1.09, p=0.067) did not significantly differ among HC users when compared to patients using BM, when controlling for other risk factors using multivariate logistic regression. CONCLUSIONS: The use of HC during postmolar follow-up or GTN treatment does not seem to increase the risk of GTN or its severity and does not postpone the normalization of hCG levels.

A twin pregnancy with a hydatidiform mole and a coexisting live fetus: prenatal diagnosis, treatment, and follow-up.

Twin molar pregnancy with a hydatidiform mole and a coexisting live fetus is a rare form of gestational trophoblastic disease associated with an increased risk of obstetric complications and poor perinatal outcome. Prenatal diagnosis is essential for couple counseling and follow-up in Tertiary Reference Centers. Magnetic resonance imaging is important for the diagnostic differentiation of placental mesenchymal dysplasia and exclusion of myometrial invasion. Here we present a case of twin molar pregnancy with a hydatidiform mole and a coexisting live fetus diagnosed at gestational week 14 using two-dimensional (2D) and three-dimensional (3D) ultrasound and magnetic resonance imaging. We also describe the obstetric management and postmolar follow-up.