Evolution of Treatment Strategies for Gestational Trophoblastic Neoplasia: Chemotherapy, Immunotherapy, and Molecular Targeted Therapy.

OPINION STATEMENT: In addressing Gestational Trophoblastic Neoplasia (GTN), it is imperative to acknowledge the evolving landscape of treatment options, especially in light of the challenges posed by traditional methods. While historically, surgical interventions, radiation therapy, and chemotherapeutic agents have been the mainstays, the emergence of resistance and high-risk scenarios necessitates a reevaluation of our therapeutic approaches. Our review highlights the promising advancements in immunotherapy and molecular targeted therapy as viable alternatives for GTN management. The introduction of immune checkpoint inhibitors and kinase inhibitors offers a paradigm shift, particularly for patients resistant to conventional chemotherapy regimens. These novel therapies not only exhibit efficacy but also demonstrate manageable toxicity profiles, particularly in high-risk cases. However, integrating these innovative treatments into established international guidelines presents a formidable task. As we move forward, it is imperative that future research not only prioritizes fertility preservation but also rigorously evaluates long-term toxicity implications. International collaboration becomes pivotal in addressing the nuances of this rare and complex disease. In conclusion, our review underscores the need for a nuanced approach to GTN treatment, one that prioritizes reduced toxicity and improved quality of life. By embracing the advancements in immunotherapy and molecular targeted therapy, we can pave the way for more effective and patient-centered care in the management of GTN.

Expert Pathology for Gestational Trophoblastic Disease: Towards an International Multidisciplinary Team Meeting.

BACKGROUND: Gestational trophoblastic disease (GTD), comprising hydatidiform moles and gestational trophoblastic tumours, is extremely rare. Exact diagnosis is crucial to indicate the appropriate treatment and to prevent complications. The scarcity and variability in the number of cases available for reporting, lack of specialised training in GTD, and non-existence of refresher courses implies that the pathologist dealing with these rare and, at times, extremely challenging cases is not completely confident in their diagnosis. OBJECTIVES: The objective of this study was to explore the benefits of implementation of an international multidisciplinary conference (virtual) to aid diagnosis of difficult cases and support clinical management of GTD. METHODS: A short survey was circulated to all 46 members of the EOTTD pathology and genetics working party and further spread to other colleagues who practice GTD. This showed that the pathologists and geneticists working with GTD patients do not feel adequately supported and equipped with dealing with these rare diseases. OUTCOME: Virtual cross-border multidisciplinary team meetings (MDTs) were initiated in April 2022, bringing together participants from 11 European countries on a bi-yearly basis. Mean numbers of 3 patients are discussed during the MDTs followed by 3-4 quality assessment cases. A participant survey was conducted at the end of virtual meeting with an average satisfaction rate of 9.5. The pathologists felt supported and benefited from networking and clinical collaboration. CONCLUSIONS AND OUTLOOK: This international MDT continues to provide support in managing the uncertainty with difficult and rare cases and enhances the pathologists training and experience. The frequency of meetings and the number of cases discussed per meeting will be increased in 2023 given the positive response. This will empower individuals and organisations to work together and improve diagnosis and the prognosis for these young patients.

Clinical Presentation, Treatment Outcomes, and Resistance-related Factors in South American Women with Low-risk Postmolar Gestational Trophoblastic Neoplasia / Apresentação clínica, resultados do tratamento e fatores relacionados à resistência em mulheres sul-americanas com neoplasia trofoblástica gestacional pós-molar de baixo risco

Abstract Objective There are few multinational studies on gestational trophoblastic neoplasia (GTN) treatment outcomes in South America. The purpose of this study was to assess the clinical presentation, treatment outcomes, and factors associated with chemoresistance in low-risk postmolar GTN treated with first-line single-agent chemotherapy in three South American centers. Methods Multicentric, historical cohort study including women with International Federation of Gynecology and Obstetrics (FIGO)-staged low-risk postmolar GTN attending centers in Argentina, Brazil, and Colombia between 1990 and 2014. Data were obtained on patient characteristics, disease presentation, and treatment response. Logistic regression was used to assess the relationship between clinical factors and resistance to first-line single-agent treatment. A multivariate analysis of the clinical factors significant in univariate analysis was performed. Results A total of 163 women with low-risk GTN were included in the analysis. The overall rate of complete response to first-line chemotherapy was 80% (130/163). The rates of complete response to methotrexate or actinomycin-D as first-line treatment, and actinomycin-D as second-line treatment postmethotrexate failure were 79% (125/157), 83% (⅚), and 70% (23/33), respectively. Switching to second-line treatment due to chemoresistance occurred in 20.2% of cases (33/163). The multivariate analysis demonstrated that patients with a 5 to 6 FIGO risk score were 4.2-fold more likely to develop resistance to first-line single-agent treatment (p= 0.019). Conclusion 1) At presentation, most women showed clinical characteristics favorable to a good outcome, 2) the overall rate of sustained complete remission after first-line single-agent treatment was comparable to that observed in developed countries, 3) a FIGO risk score of 5 or 6 is associated with development of resistance to first-line single-agent chemotherapy.

Resumo Objetivo Existem poucos estudos multinacionais sobre os resultados do tratamento da neoplasia trofoblástica gestacional (NTG) na América do Sul. O objetivo deste estudo foi avaliar a apresentação clínica, os resultados do tratamento e os fatores associados a casos de quimiorresistência em NTG pós-molar de baixo risco tratados com quimioterapia de agente único de primeira linha em três centros sul-americanos. Métodos Estudo multicêntrico de coorte histórica incluindo mulheres com NTG pós-molar de baixo risco com estadiamento International Federation of Gynecology and Obstetrics (FIGO) em centros de atendimento na Argentina, Brasil e Colômbia entre 1990 e 2014. Foram obtidos dados sobre as características do paciente, apresentação da doença e resposta ao tratamento. A regressão logística foi usada para avaliar a relação entre fatores clínicos e resistência ao tratamento de primeira linha com agente único. Foi realizada uma análise multivariada dos fatores clínicos significativos na análise univariada. Resultados Cento e sessenta e três mulheres com NTG de baixo risco foram incluídas na análise. A taxa global de resposta completa à quimioterapia de primeira linha foi de 80% (130/163). As taxas de resposta completa ao metotrexato ou actinomicina-D como tratamento de primeira linha e actinomicina-D como tratamento de segunda linha após falha do metotrexato foram 79% (125/157), 83% (⅚) e 70% (23/33), respectivamente. A mudança para o tratamento de segunda linha por quimiorresistência ocorreu em 20,2% dos casos (33/163). A análise multivariada demonstrou que pacientes com pontuação de risco FIGO de 5 a 6 foram 4,2 vezes mais propensos a desenvolver resistência ao tratamento com agente único de primeira linha (p= 0,019). Conclusão 1) Na apresentação, a maioria das mulheres demonstrou características clínicas favoráveis a um bom resultado, 2) a taxa geral de remissão completa sustentada após o tratamento de primeira linha com agente único foi comparável à de países desenvolvidos, 3) um escore de risco FIGO de 5 ou 6 está associado ao desenvolvimento de resistência à quimioterapia de agente único de primeira linha.

Guideline No. 408: management of gestational trophoblastic diseases

This guideline reviews the clinical evaluation and management of gestational trophoblastic diseases, including surgical and medical management of benign, premalignant, and malignant entities. The objective of this guideline is to assist health care providers in promptly diagnosing gestational trophoblastic diseases, to standardize treatment and follow-up, and to ensure early specialized care of patients with malignant or metastatic disease. General gynaecologists, obstetricians, family physicians, midwives, emergency department physicians, anaesthesiologists, radiologists, pathologists, registered nurses, nurse practitioners, residents, gynaecologic oncologists, medical oncologists, radiation oncologists, surgeons, general practitioners in oncology, oncology nurses, pharmacists, physician assistants, and other health care providers who treat patients with gestational trophoblastic diseases. This guideline is also intended to provide information for interested parties who provide follow-up care for these patients following treatment. Women of reproductive age with gestational trophoblastic diseases. Women diagnosed with a gestational trophoblastic disease should be referred to a gynaecologist for initial evaluation and consideration for primary surgery (uterine evacuation or hysterectomy) and follow-up. Women diagnosed with gestational trophoblastic neoplasia should be referred to a gynaecologic oncologist for staging, risk scoring, and consideration for primary surgery or systemic therapy (single- or multi-agent chemotherapy) with the potential need for additional therapies. All cases of gestational trophoblastic neoplasia should be discussed at a multidisciplinary cancer case conference and registered in a centralized (regional and/or national) database. Relevant studies from 2002 onwards were searched in Embase, MEDLINE, the Cochrane Central Register of Controlled Trials, and Cochrane Systematic Reviews using the following terms, either alone or in combination: trophoblastic neoplasms, choriocarcinoma, trophoblastic tumor, placental site, gestational trophoblastic disease, hydatidiform mole, drug therapy, surgical therapy, radiotherapy, cure, complications, recurrence, survival, prognosis, pregnancy outcome, disease outcome, treatment outcome, and remission. The initial search was performed in April 2017 and updated in May 2019. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional significant articles were identified through cross-referencing the identified reviews. The total number of studies identified was 673, with 79 studies cited in this review. The content and recommendations were drafted and agreed upon by the authors. The Executive and Board of Directors of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of Directors for the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology framework. See the online appendix tables for key to grading and interpretation of recommendations. These guidelines will assist physicians in promptly diagnosing gestational trophoblastic diseases and urgently referring patients diagnosed with gestational trophoblastic neoplasia to gynaecologic oncology for specialized management. Treating gestational trophoblastic neoplasia in specialized centres with the use of centralized databases allows for capturing and comparing data on treatment outcomes of patients with these rare tumours and for optimizing patient care.

Gestational trophoblastic neoplasia after ectopic molar pregnancy: clinical, diagnostic, and therapeutic aspects / Neoplasia trofoblástica gestacional após gestaçãomolar ectópica: aspectos clínicos, diagnósticos e terapêuticos

Abstract This report presents the case of a patient with gestational trophoblastic neoplasia after a partial hydatidiform mole formed in the Fallopian tube. Ectopic molar pregnancy is a rare condition, with an estimated incidence of 1 in every 20,000 to 100,000 pregnancies; less than 300 cases of it have been reported in the Western literature. The present report is important because it presents current diagnostic criteria for this rare condition, which has been incorrectly diagnosed in the past, not only morphologically but also immunohistochemically. It also draws the attention of obstetricians to the occurrence of ectopic molar pregnancy, which tends to progress to Fallopian tube rupture more often than in cases of ectopic non-molar pregnancy. Progression to gestational trophoblastic neoplasia ensures that patients with ectopic molar pregnancy must undergo postmolar monitoring, which must be just as thorough as that of patients with intrauterine hydatidiform moles, even if chemotherapy results in high cure rates.

Resumo Esse relato apresenta um caso de neoplasia trofoblástica gestacional após mola hidatiforme parcial ocorrida na tuba uterina. Trata-se de uma associação rara, cuja incidência estima-se de 1 em cada 20.000 a 100.000 gestações, havendomenos de 300 casos apresentados na literatura ocidental. O tema é importante porque apresenta critérios diagnósticos atuais para essa ocorrência incomum, que vinha sendo diagnosticada equivocadamente, não apenas sob o ponto de vista morfológico, como também imunohistoquímico. Da mesma forma, alerta o obstetra para a ocorrência da gravidez molar ectópica, que tende a evoluir com rotura tubária mais frequentemente do que os casos de gravidez ectópica não molar. Por fim, a evolução do caso para neoplasia trofoblástica gestacional impõe às pacientes com gravidez ectópica molar a necessidade de seguimento pós-molar tão rigoroso quanto nos casos de mola hidatiforme intrauterina, ainda que o tratamento quimioterápico determine elevadas taxas de cura.

SEOM clinical guidelines in gestational trophoblastic disease (2017)

Gestational trophoblastic disease (GTD) is a rare but curable disease. Recent improvements in diagnosis and molecular biology have resulted in changes in staging and treatment. These guidelines provide evidence-based recommendation on how to manage GTD (AU)

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Gestational Trophoblastic diseases: alternatives to biological monitoring in under-resourced settings (Two clinical observations)

Gestational trophoblastic disease (GTD) is a condition requiring regular monitoring of hormone human chorionic gonadotropin (HCG). The semi-quantitative method presented here is an alternative for monitoring in under-equipped environments. The illustration made from two clinical cases of GTD that we have followed shows that this method can be used in under-equipped settings and where the quantitative dosage is unavailable

Atualização no diagnóstico e tratamento da gravidez molar / Update on the diagnosis and treatment of molar pregnancy

A doença trofoblástica gestacional (DTG) é um termo aplicado a um grupo de tumores relacionados à gestação, caracterizado por entidades clínicas benignas (mola hidatiforme ? MH) e malignas (neoplasia trofoblástica gestacional ? NTG). Os principais desafios para o tratamento das pacientes com MH abrangem o diagnóstico precoce, esvaziamento uterino imediato e seguimento pós-molar regular com dosagem sérica de hCG, melhorando assim o prognóstico das pacientes, sua qualidade de vida e resultados reprodutivos. A atualização das estratégias diagnósticas e terapêuticas envolvidas no tratamento da DTG, foco deste trabalho, tem por objetivo melhorar esse cenário, contribuindo para o maior conhecimento sobre o assunto.

The gestational trophoblastic disease (GTD) is a term applied to a group of pregnancy related tumors, characterized by benign clinical entities (hydatidiform mole ? HM) and malignant ones (gestational trophoblastic neoplasia ? GTN). The main challenges for treatment of patients with HM include early diagnosis, immediate uterine evacuation and systematic post-molar follow-up with seric dosage of hCG, improving the prognosis of patients, their quality of life and reproductive outcomes. The focus of the present paper is the update of diagnostic and therapeutic strategies involved in the treatment of GTD aiming to improve this scenario to enhance the knowledge on the subject.

Neoplasia trofoblástica gestacional após normalização espontânea da gonadotrofina coriônica humana em paciente com mola hidatiforme parcial / Gestational trophoblastic neoplasia after spontaneous normalization of human chorionic gonadotropin in patient with partial hydatidiform mole

Neste relato, é apresentado um caso de neoplasia trofoblástica gestacional após normalização espontânea de gonadotrofina coriônica humana em paciente com mola hidatiforme parcial. Trata-se da segunda ocorrência publicada desse evento e a primeira em que há comprovação imuno-histoquímica. No bojo dessa apresentação, ademais de mostrar o tratamento para essa intercorrência da gravidez, discute-se a possibilidade de redução da duração do seguimento pós-molar, assim como estratégias para o precoce reconhecimento da neoplasia trofoblástica gestacional após a remissão espontânea da gravidez molar.

We report here a case of gestational trophoblastic neoplasia after spontaneous normalization of human chorionic gonadotropin in a patient with a partial hydatidiform mole. This is the second occurrence of this event to be reported and the first one with proven immunohistochemical evidence. Besides showing the treatment for this pregnancy complication, this case report discusses the possibility of reducing the duration of post-molar follow-up, as well as strategies for early recognition of gestational trophoblastic neoplasia after spontaneous remission of molar pregnancy.

Enfermedad trofoblástica gestacional (ETG): experiencia en el Instituto Nacional de Enfermedades Neoplásicas 1980-2005 / Gestational trophoblastic disease (GTD): experience at the National Institute of Neoplastic Diseases 1980-2005

Objetivo.- Evaluar el comportamiento clínico y los resultados del tratamiento de la ETG en el INEN en el periodo comprendido entre los años 1980 y 2005. Material y métodos.- Estudio retrospectivo realizado en el INEN entre ene-1980 y dic-2005. Se revisaron 595 historias clínicas, recopilando información clínica, tratamientos administrados, toxicidades reportadas, tasa de respuestas y sobrevida global, para los cálculos estadísticos se utilizaron las pruebas de Kaplan-Meier. Resultados.- Entre ene-1980 a dic-2005, fueron admitidas en el INEN 595 pacientes con diagnóstico de ETG: Mola Hidatiforme 254 casos (42.7%), Coriocarcinoma 201 casos (33.8%) y Mola invasiva 41 casos (6.8%) no se reportaron casos de Tumor del sitio de inserción placentaria. Las localizaciones más frecuentes de metástasis fueron: pulmón: 67.3%, vagina: 17.9%, sistema nervioso central: 8.7%, e hígado: 5.1%. Se catalogó las pacientes de acuerdo al Sistema Score de FIGO: Bajo riesgo (score 1-6) 348 pacientes (58.5%) y Alto riesgo (score >6) 247 pacientes (41.5%). El tratamiento fue con monodroga 50.4% y con poliquimioterapia 49.6%. Pacientes de bajo riesgo que recibieron tratamiento con Metotrexate VO obtuvieron respuesta completa en 66.1% de los casos y 97% de sobrevida global a 20 años. Las pacientes de alto riesgo lograron respuesta completa con MAC: 32.5 %, MEC 36.8 %, EMA-CO 50%, BEP 25%. La población de alto riesgo se dividió en dos sub-grupos de acuerdo al score mayor de 12 y menor de 12, hallándose diferencias en la sobrevida global a 20 años de 80% para la población con score menor de 12 y 48% para el grupo con score mayor de 12 quienes presentaron metástasis en hígado y cerebro en 26.5%. Conclusiones.- ETG es una neoplasia altamente curable. Las pacientes de bajo riesgo que recibieron tratamiento con Metotrexate VO, lograron sobrevida global a 20 años de 97%. Existe diferencia en la sobrevida global entre pacientes de alto riesgo con score menor de 12 (80%).

Objective.-To evaluate the clinical behavior and results of treatment of gestational trophoblastic disease at the INEN between 1980 to 2005. Material and methods.- This is a retrospective analysis from January 1980 to December 2005. Evaluation included patient clinical characteristics, treatment, toxicity, response to therapies and survival. Descriptive statistics and Kaplan-Meier for survival analysis was also determined. Results.- 595 patients with GTD were evaluated from January 1980 to December 2005. Hydatidi form mole 254 (42.7%) choriocarcinoma 201 (33.8%) invasive mole 41 (6.8%), no cases with placental insertion trophoblastic tumor (PSTT) were seen. Sites of metastasis were: lung 67.3%, vagina 17.9%, brain 8.7%, liver 5.1%. Among these patients, 247 (41.5%) were categorized by FIGO scoring System as high risk (score >6) and 348 (58.5%) as low risk (score 1-6). The low risk patients whose received treatment with Metotrexate achieved complete remission in 66.1% of cases and the overall survival rate at 20 years was 97%. Patients with high risk who received treatment with: MAC, MEC, EMACO and BEP achieved complete remission in 32.5%, 36.8%, 50% and 25% respectively. High risk populations were divided in two groups according to score > 12 and 12, who developed liver and brain metastasis in 26.5%. The overall survival rate at 20 years, for those with score 12,48%. Conclusions.-Gestational trophoblastic disease is a highly curable neoplasia. Patients with low risk, who received Metotrexate, achieved 97% overall survival rate at 20 years. There are differences inoverall survival rate between patients of high risk those with score 12 (48%) the latter presented brain and liver metastasis. lt is important to define the best treatment for this group of patients.