Tese Completa 12DEZ2021 v1

UNIVERSIDADE FEDERAL FLUMINENSE FACULDADE DE MEDICINA
PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS MÉDICAS
PAULO ALEXANDRE RIBEIRO MORA
AVALIAÇÃO DA UTILIZAÇÃO DE CARBOPLATINA OU ETOPOSIDE EM

SUBSTITUIÇÃO DA ACTINOMICINA-D NO TRATAMENTO DA NEOPLASIA
TROFOBLÁSTICA GESTACIONAL DE BAIXO RISCO RESISTENTE AO
METOTREXATO
NITERÓI - RJ
2021

METOTREXATO
Tese submetida ao Programa de Pós-Graduação

em Ciências Médicas da Universidade Federal
Fluminense como parte dos requisitos
necessários à obtenção do Grau de Doutor.
Área de Concentração: Ciências Médicas
Orientador: Prof. Dr. ANTÔNIO RODRIGUES BRAGA NETO

http://lattes.cnpq.br/7557971069321691
NITERÓI – RJ
2021

METOTREXATO
Tese submetida ao Programa de Pós-Graduação

em Ciências Médicas da Universidade Federal
Fluminense como parte dos requisitos
necessários à obtenção do Grau de Doutor.
Área de Concentração: Ciências Médicas
BANCA EXAMINADORA
Prof. Dr.
Prof. Dr.
Prof. Dr.
Prof. Dr.
NITERÓI – RJ
2021
Ao meu avô, Fernando de Castella e Aragão Mora, por ter acreditado em mim, mas
principalmente pelo exemplo de ser humano que me inspirou.
Agradecimentos
Ao meu orientador Antônio Rodrigues Braga Neto, pela confiança, conhecimento

interminável e compartilhado, e amizade dedicados de forma inabalável.
Ao Grupo de Doença Trofoblástica Gestacional da Maternidade Escola da UFRJ e do
Hospital Universitário Antônio Pedro da UFF, às Professoras Elza Maria Hartmann Uberti e
Sue Yazaki Sun, respectivamente do Centro de Doença Trofoblástica da Irmandade da Santa
Casa de Porto Alegre (RS) e do Centro de Doença Trofoblástica da Universidade Federal de
São Paulo (SP), pelo acolhimento, dedicação e inestimável contribuição na construção deste
trabalho.
À Associação Brasileira de Doença Trofoblástica Gestacional (ABDTG) pelo apoio e
companheirismo em todas as fases do meu aprendizado da doença trofoblástica.
À Seção de Oncologia Clínica do Hospital do Câncer Unidade II, do Instituto Nacional
do Câncer, pela parceria e partilha de conhecimentos, e à Equipe da Direção do INCA e do
HCII, pelo estímulo, apoio, suporte e amizade: meus irmãos e irmãs de armas nesse trajeto.
A toda Direção e corpo clínico da COI/Oncologia Américas pela gentileza e apoio
fundamentais.
Ao Programa de Pós-graduação em Ciências Médicas da Universidade Federal
Fluminense, que me aceitou como aluno, aos professores pelos ensinamentos, aos funcionários
pela incansável orientação, e aos colegas do curso pelo incentivo e convívio.
À minha mãe Fernanda, aos meus irmãos e a toda minha família, por todo apoio, amor
e momentos inesquecíveis.
Aos meus filhos Paula, Gabriela e Arthur, por darem toda felicidade e amor que um pai
pode querer de seus filhos e aos meus enteados Mariana e Pedro, pela amizade e
companheirismo que dividem comigo.
À minha esposa Roberta por manter a fé e o amor, e porque “tudo, tudo, tudo, tudo que
nós tem é nós”.
“Aplicarei os regimes para o bem do doente segundo o meu poder e entendimento, nunca para
causar dano ou mal a alguém.”
Hipócrates (460-377 A.C.)
Resumo
Objetivo: Comparar o desfecho clínico de mulheres com NTG de baixo risco após
resistência a metotrexato e ácido folínico (MTX/AF), tratadas alternativamente com
Actinomicina D (Act-D), Carboplatina ou Etoposide.
Métodos: Foram comparadas variáveis demográficas, clínicas e laboratoriais entre as
coortes retrospectivas que incluíram pacientes que não responderam ao tratamento com
MTX/FA em primeira linha para NTG de baixo risco, sendo então tratadas com Actinomicina
D (Act-D), Carboplatina ou Etoposide, de janeiro de 2010 a dezembro de 2017. O desfecho
primário foi a ocorrência de remissão após quimioterapia em segunda linha e os desfechos
secundários foram as toxicidades, número de ciclos necessários para atingir a remissão de NTG,
tempo para remissão, duração do acompanhamento e ocorrência de recidiva e morte.
Resultados: Das 356 pacientes com NTG de baixo risco tratadas com MTX/FA, 75
(21,1%) desenvolveram resistência, das quais 40 (53,3%) receberam Act-D, 23 (30,7%),
carboplatina, e 7 (9,3%), etoposide. Embora as pacientes que receberam quimioterapia de
agente único como regime de segunda linha tenham apresentado características clínicas e
tratamento primário comparáveis, aquelas tratadas com Act-D (80%, p = 0,033) ou etoposide
(71,4%, p = 0,025) apresentaram taxas de remissão mais altas comparados à carboplatina
(47,8%). Apenas 29% das pacientes tratadas com carboplatina receberam os ciclos de
quimioterapia sem atraso, em comparação com o Act-D (98%, p <0,001) ou etoposide (85%,
p = 0,009). As pacientes tratadas com carboplatina apresentaram significativamente mais
toxicidade hematológica, especialmente anemia (30,4%, p = 0,008), linfopenia (47,7%, p
<0,001) e trombocitopenia (43,4%, p <0,001), além de maior ocorrência de neutropenia febril
(14,4%, p = 0,044) e vômitos (60%, p <0,001) do que naquelas que receberam Act-D (5%,
zero, 2,5%, zero, 10%, respectivamente).
Conclusão: Provavelmente devido à toxicidade hematológica grave, a carboplatina não
apresentou uma taxa de resposta clínica satisfatória, o que adiou a quimioterapia. Nossos
resultados reforçam a preferência pela Act-D como agente de segunda linha em pacientes com
NTG de baixo risco, após resistência ao MTX/AF.
Palavras-chave: Neoplasia trofoblástica gestacional; Resistência ao metotrexato;
Actinomicina-D; Carboplatina; Etoposide.
Abstract
Objective: To compare the clinical outcome of women with low-risk NTG after
resistance to methotrexate and folinic acid (MTX/AF), treated alternatively with Actinomycin
D (Act-D), Carboplatin or Etoposide.
Methods: Demographic, clinical, and laboratory variables were compared among
retrospective cohorts that included patients who did not respond to first line MTX/FA
treatment for low-risk NTG, then treated with Actinomycin D (Act-D), Carboplatin or
Etoposide, from January 2010 to December 2017. The primary outcome was the occurrence
of remission after second-line chemotherapy and the secondary outcomes were toxicities,
number of cycles needed to reach NTG remission, time to remission, duration of follow-up
and occurrence of relapse and death.
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%, < b 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.
Keywords: Gestational trophoblastic neoplasia; Resistance to methotrexate;
Actinomycin-D; Carboplatin; Etoposide.
Lista de Figuras
Figura 1 - Diagrama resumindo a divisão da população do estudo 35

Lista de Tabelas
Tabela 1 - Estadiamento e Classificação da FIGO/OMS para Neoplasia 20

Trofoblástica Gestacional (NTG).
Tabela 2 - Taxas de remissão primária na Neoplasia Trofoblástica Gestacional de 22

baixo risco de acordo com o regime utilizado.
Tabela 3 - Características dos pacientes com neoplasia trofoblástica gestacional 36

de baixo risco resistentes ao MTX/AF, de acordo com o esquema de segunda linha.
Tabela 4 - Perfil clínico e terapêutico de pacientes com falha ao MTX/AF para o 37

tratamento de neoplasia trofoblástica gestacional de baixo risco, de acordo com o
esquema de tratamento de segunda linha.
Tabela 5 - Desfechos dos esquemas de tratamento de segunda linha de pacientes 39

com neoplasia trofoblástica gestacional de baixo risco, após a falha a MRX/AF.
Tabela 6 - Eventos adversos secundários ao regime de segunda linha para o 41

tratamento de neoplasia trofoblástica gestacional de baixo risco, após a
resistência a metotrexato/ácido folínico, graduado de acordo com o
Critério Comum de Toxicidade (CTC) para Eventos Adversos, versão 5.0 (2017).
Tabela 7 - Comparação Indireta de Dados entre os Estudos de Carboplatina em 44

Segunda Linha para NTG Resistente ao MTX.
Lista de Abreviaturas
Act-D Actinomicina D
AUC Area Under Curve (Área Sob a Curva)
CCA Coriocarcinoma
COI Clínicas Oncológicas Integradas (Oncologia Américas)
CTC Common Toxicity Criteria (Critério Comum de Toxicidade)
CTCAE Common Terminology Criteria for Adverse Events (Critério Comum de

Terminologias para Eventos Adversos).
DTG Doença Trofoblástica Gestacional
EMA-CO Etoposide, Metotrexato, Actinomicina D, Ciclofosfamida e Vincristina

(Oncovin®)
FA Ácido Folínico
FIGO International Federation of Gynecology and Obstetrics (Federação

Internacional de Ginecologia e Obstetrícia)
G-CSF Granulocyte-colony stimulating factor (Fator de estimulação de colônias de

granulócitos)
GFR Glomerular Filtration Rate (Taxa de Filtração Glomerular)
hCG Gonadotrofina Coriônica Humana
HCII Hospital do Câncer Unidade II (INCA)
HTA Histerectomia Total Abdominal
IC Intervalo de Confiança
INCA Instituto Nacional de Câncer
MI Mola Invasora
mmHg Milímetros de Mercúrio
MTX Metotrexato
ng/dL Nanogramas por Decilitro
NR Não Reportado
NTG Neoplasia Trofoblástica Gestacional
OMS Organização Mundial da Saúde
QT Quimioterapia
RCOG Royal College of Obstetricians and Gynaecologists (Colégio Inglês de

Obstetras e Ginecologistas)
RNM Ressonância Nuclear Magnética
RX Radiografia
TC Tomografia Computadorizada
TE/TP Paclitaxel-Etoposide e Paclitaxel-Cisplatina
TGO Transaminase glutâmico oxaloacética/aspartato aminotransferase (AST)
TGP Transaminase glutâmico pirúvica/alanina aminotrasnferase (ALT)
TTE Tumor Trofoblástico Epitelioide
TTSP Tumor Trofoblástico do Sítio Placentário
UFF Universidade Federal Fluminense
UFRJ Universidade Federal do Rio de Janeiro
UI/L Unidades Internacionais por Litro
USTV Ultrassonografia Transvaginal

Sumário
1. Introdução 15
1.1 Classificação e Estadiamento 18
1.2 Tratamento Sistêmico 21
1.3 Tratamento da NTG com Quimiorresistência ao MTX 24
2. Objetivos 26
3. Material e Métodos 27
2.1 Desenho do Estudo 27
2.2 Participantes do Estudo 27
2.3 Amostragem 28
2.4 Diagnóstico de NTG 29
2.5 Estadiamento, Fatores de risco e Tratamento de NTG 29
2.6 Desfechos 31
2.7 Variáveis 32
2.8 Análise Estatística 33
4. Resultados 34
5. Discussão 42
6. Conclusões 47
7. Referências Bibliográficas 48
8. Anexos 59
9. Artigos Publicados 75
15
1. Introdução
A neoplasia trofoblástica gestacional (NTG) é o termo utilizado para designar lesões

malignas que se originam das vilosidades coriais e do trofoblasto extraviloso. Estão sob esse
epíteto quatro formas clínicas distintas, com diferentes graus de proliferação, invasão e
disseminação, representadas pela mola invasora (MI), coriocarcinoma (CCA), tumor
trofoblástico do sítio placentário (TTSP) e tumor trofoblástico epitelioide (TTE) (Goldstein e
Berkowitz, 2012; Lurain, 2010; Lurain, 2011; RCOG, 2021; Seckl, 2013). Aproximadamente
50% dos casos de NTG originam-se de gestações molares, 25% de abortamentos ou gravidez
ectópica e 25% de gestações de termo ou pretermo (Goldstein e Berkowitz, 2012). Já o TTSP
e o TTE seguem gestações a termo ou abortamentos não molares em 95% das vezes (Osborne
e Dodge, 2012). O maior estudo epidemiológico realizado no Brasil observou evolução para
NTG em 24,6% das pacientes com mola hidatiforme completa e em 7,6% após mola
hidatiforme parcial (Braga et al., 2014). A maior parte dos casos de NTG é representada pela
MI e CCA. São formas da doença que cursam com elevados níveis de gonadotrofina coriônica
humana (hCG), altamente responsivas à quimioterapia (QT), com taxas de cura superiores a
90% (Goldstein e Berkowitz, 2012). Por outro lado, o TTSP e o TTE, mais raros, têm produção
escassa de hCG (Sung et al., 2013) e são relativamente resistentes à QT, tornando a cirurgia sua
primeira linha de tratamento, particularmente nos casos não metastáticos (Goldstein e
Berkowitz, 2012).
A apresentação clínica da NTG é variável, dependente do evento gestacional que a
originou, da extensão da doença e de seu diagnóstico anatomopatológico (Goldstein e
Berkowitz, 2012; Lurain, 2010). Útero aumentado de volume, sangramento transvaginal
irregular e persistência dos cistos tecaluteínicos nos ovários são sinais sugestivos de NTG
(Goldstein e Berkowitz, 2012). No entanto, mais de 50% das pacientes com NTG pós-molar
não apresentam qualquer achado clínico e o diagnóstico é feito somente pelo platô ou aumento
do hCG sérico dosado durante o seguimento após o esvaziamento uterino (Khoo et al., 2010).
Quando o CCA está associado a antecedente gestacional não molar, não há sinais e
sintomas típicos, e estes são, em sua maioria, relacionados à invasão tumoral no útero ou sítios
de metástases, notadamente nos pulmões e na pelve (Goldstein e Berkowitz, 2012; Lurain,
2010).
A disseminação da NTG ocorre via hematogênica, mais frequentemente para pulmão
(80%), vagina (30%), cérebro (10%) e fígado (10%) (Hui et al., 2005). As metástases
16
pulmonares são, em geral, assintomáticas; porém, quando extensas, podem provocar dispneia,
tosse, hemoptise e dor torácica (Goldstein e Berkowitz, 2012; Lurain, 2010).
Nódulos vaginais metastáticos ocorrem mais frequentemente nos fórnices e região
suburetral. Podem causar leucorreia purulenta e sangramento de difícil controle, uma vez que
apresentam exuberante vascularização (Berkowitz e Goldstein, 2009; Lurain, 2010).
Sangramento resultante de perfuração uterina ou lesões metastáticas cursam com dor
abdominal, hemoptise, melena e sinais e sintomas de aumento da pressão intracraniana, como
cefaleia, convulsões, alterações na fala, distúrbios visuais e hemiplegia (Goldstein e Berkowitz,
2012; Lurain, 2010). É a NTG perfundida por circulação anômala, aberrante, com vasos frágeis
que apresentam tendência ao sangramento. Pelo elevado risco de hemorragia, biópsias de sítios
metastáticos não são recomendadas (Berkowitz e Goldstein, 2009).
Em quase todas as pacientes com TTSP e TTE há sangramento uterino anormal após
longo período do evento gestacional anterior (Sung et al., 2013). São descritas também, ainda
que em raras apresentações, virilização e síndrome nefrótica (Goldstein e Berkowitz, 2012;
Hyman et al., 2013; Lurain, 2010).
Uma vez que os sintomas podem ser mínimos ou até mesmo ausentes, e o antecedente
gestacional remoto, o diagnóstico de NTG deve ser suspeitado em toda mulher em idade
reprodutiva com sintomas pulmonares ou sistêmicos inexplicáveis, notadamente na presença
de metástases com sítio desconhecido de neoplasia primária (Berkowitz e Goldstein, 2009).
Mediante suspeita ou diante do diagnóstico estabelecido de NTG, a avaliação da
presença de metástases e fatores de risco é mandatória. Além de anamnese e exame físico
minuciosos, deve-se obter hemograma completo, coagulograma, função hepática e renal,
tipagem sanguínea, fator RH e dosagem de hCG (Goldstein e Berkowitz, 2012; RCOG, 2021;
Soper et al., 2004).
A avaliação sérica quantitativa de hCG é o pilar do diagnóstico da NTG, cujos critérios
diagnósticos são apresentados abaixo (FIGO, 2018) (Braga et al., 2019):
1) Quatro valores ou mais de hCG em platô (± 10%) em um período superior a 3 semanas, ou
seja, nos dias 1,7,14 e 21;
2) Aumento (>10%) nos níveis de hCG por 3 medidas consecutivas ou mais, ao menos por 2
semanas, ou seja, nos dias 1,7 e 14;
3) Diagnóstico histológico de coriocarcinoma;
Cabe citar o estudo de Agarwal e colaboradores (2012) em que se avaliou o rigoroso
seguimento clínico-laboratorial de pacientes com níveis elevados de hCG por 6 meses ou mais
após esvaziamento uterino. No mesmo sentido, Braga e colaboradores (2016) demonstraram
17
que os níveis elevados, porém decrescentes, de hCG mesmo após 6 meses não necessitavam de
tratamento com quimioterapia. O resultado dessa investigação mostrou que o acompanhamento
prolongado é aceitável, evitando-se a utilização desnecessária de quimioterápicos. As
conclusões levaram à mudança nos critérios diagnósticos da FIGO em 2018 (Ngan et al., 2018).
Ademais, podem ser incluídos como critérios diagnósticos de NTG os seguintes
elementos clínicos considerados pelo Charing Cross Trophoblastic Disease Center como
indicativos de tratamento: hemorragia vaginal abundante, evidência de hemorragia
gastrointestinal ou intraperitoneal, evidência de metástase no cérebro, fígado ou trato
gastrointestinal e opacidades radiológicas maiores que dois centímetros na radiografia (RX) de
tórax (Seckl et al., 2013).
A ultrassonografia transvaginal (USTV) é ferramenta diagnóstica fundamental para o
diagnóstico de NTG e os vários tipos da doença podem apresentar aparência semelhante nos
exames de imagem (Kani et al., 2012). Massa miometrial focal é a imagem mais comum. Pode
ser uniformemente hipo ou hiperecogênica, complexa ou ainda, multicística. Espaços anecoicos
intramiometriais resultam de hemorragia e necrose dos tecidos ou espaços vasculares. Na
doença mais extensa, pode-se observar também útero volumoso, heterogêneo e lobulado ou
massa pélvica indiferenciada (Allen et al., 2006; Kani et al., 2012).
O mapeamento com Doppler colorido pode demonstrar vascularização intensa e caótica,
com perda da continuidade dos vasos. O fluxo sanguíneo apresenta alta velocidade e baixa
resistência, padrão inverso ao das artérias miometriais normais. Exceção se faz ao TTSP, que
pode ser hipo ou hipervascular (Kani et al., 2012).
A RX de tórax é o método de imagem recomendado pela FIGO para avaliação de
metástases pulmonares. Contudo, até 41% das pacientes com metástases pulmonares na
tomografia computadorizada (TC) possuem RX de tórax normal. São as micrometástases, mais
bem avaliadas pela TC, porém, com importância questionável, uma vez que sua presença não
parece afetar a sobrevida a longo prazo (Allen et al., 2006). Outros exames de imagem, como
ressonância nuclear magnética (RNM) e TC não fazem parte da avaliação rotineira da NTG,
ficando reservados a casos duvidosos ou suspeita de metástases; a TC é o método mais
adequado para avaliação dos sítios mais comuns de metástases, exceto para lesões vaginais e
cerebrais, mais bem vistas à RNM (Kani et al., 2012).
Apesar de existirem poucos estudos a respeito, a TC com emissão de pósitrons parece
ser capaz de identificar sítios de doença metabolicamente ativa não evidenciada por outros
exames. Outrossim, também pode ser útil na diferenciação entre cicatrizes uterinas, fibrose e
doença ativa (Kani et al., 2012).
18
Em geral, a NTG é altamente responsiva à quimioterapia e possui um marcador

tumoral sensível, a gonadotrofina coriônica humana (hCG), que permite monitorar a resposta
ao tratamento, assegurando a remissão da doença (Ngan et al., 2018). Como a NTG é
incomum, as pacientes com essa doença podem se beneficiar do tratamento em Centros de
Referência, onde as taxas de sobrevida se aproximam de 100%, principalmente quando a NTG
é diagnosticada precocemente (Dantas et al., 2012). A escolha da quimioterapia para a NTG é
baseada no estadiamento da Federação Internacional de Ginecologia e Obstetrícia (FIGO) e
no sistema de escore de risco da Organização Mundial da Saúde (OMS), que avalia fatores
prognósticos para resistência à terapia com agente único (Ngan et al., 2018).
1.1 Classificação e Estadiamento
Ao longo do tempo, diversos estadiamentos, classificações e sistemas prognósticos

foram utilizados para NTG em todo o mundo, o que tornava difícil a comparação entre os
resultados de trabalhos realizados em diferentes centros de referência. Frente à necessidade de
uma linguagem universal, critérios comuns de tratamento e um sistema de estadiamento
mundialmente aceito, em 2002, a Federação Internacional de Ginecologia e Obstetrícia (FIGO)
publicou um novo sistema de classificação para NTG (Tabela 1), que combinou seu antigo
sistema de estadiamento anatômico com um sistema modificado de pontuação de fatores de
risco da Organização Mundial da Saúde (OMS) (FIGO Oncology Committee, 2002; Goldstein
e Berkowitz, 2012).
Nessa nova classificação, excluiu-se grupo sanguíneo dos fatores de risco, atribuiu-se à
metástase hepática pontuação 4 em vez de 3 e foi eliminado o grupo doença de médio risco.
Utilizando-se esse sistema, a paciente poderá ter seu tumor classificado em dois grupos: NTG
de baixo risco, se pontuação igual ou inferior a 6 e NTG de alto risco, se pontuação igual ou
superior a 7 (Figo Oncology Committee, 2002; Soper et al., 2004). O estadiamento é designado
por um número romano seguido por um número arábico, que representam o estadiamento
anatômico da FIGO e o escore modificado da OMS, respectivamente. TTSP e TTE são
classificados separadamente (Goldstein e Berkowitz, 2012).
O tratamento baseia-se no escore total dos fatores de risco, o qual representa a chance
de as pacientes desenvolverem resistência aos medicamentos de primeira linha com agente
único (Goldstein e Berkowitz, 2012; Seckl et al., 2013). Pacientes com doença em estágio I, II
ou III e escore de risco FIGO/OMS ≤ 6 são consideradas NTG de baixo risco e são tratadas
com quimioterapia de agente único, geralmente, metotrexato e resgate de ácido folínico
19
(MTX/FA) ou actinomicina-D (Act-D), com taxas de remissão primária variando de 70 a 90%

(Ngan et al., 2018). O risco de resistência a um regime de agente único é aumentado entre
pacientes com NTG de baixo risco, com escores de risco FIGO/OMS de 5-6 e diagnóstico
clínico-patológico de coriocarcinoma. Mesmo nesses casos, a quimioterapia de resgate pode
curar mais de 90% dessas pacientes (Ngan et al., 2018).
20
Tabela 1 – Estadiamento e Classificação da FIGO/OMS para Neoplasia Trofoblástica

Gestacional (NTG)
NTG: estadiamento e classificação FIGO (Washington, 2000)

Estadiamento Anatômico da FIGO
Estadio I: Doença confinada ao útero
Estadio II: Doença que se estende além do útero, porém limitada a estruturas genitais
Estadio III: Doença que se estende aos pulmões com ou sem envolvimento do trato
genital
Estadio IV: Todos os outros sítios metastáticos
Sistema de escore prognóstico da OMS modificado pela FIGO

Fatores Pontuação
prognósticos 0 1 2 4
Idade <40 ≥40 - -
Gestação anterior Mola Aborto Termo -
Intervalo (meses)* <4 4-6 7-12 > 12
HCG sérico pré- <103 103 a < 104 104 a < 105 > 105
tratamento
(mUI/mL)
Maior tumor, <3 3a4 ≥5 -
incluindo útero (cm)
Local de metástases Pulmão Baço, Rim TGI Cérebro,
fígado
Número de - 1-4 5-8 >8
metástases
Falha à primeira - - Monoterapia 2 drogas ou
quimioterapia mais
* Intervalo (em meses) entre o fim do antecedente gestacional (quando conhecido) e o início
dos sintomas. (Figo Oncology Committee, 2002)
21
1.2 Tratamento Sistêmico
Há 50 anos, antes da introdução da QT no manejo da NTG, a taxa de mortalidade por

mola invasora chegava a 15%, ocorrendo mais frequentemente por hemorragia, sepse,
fenômenos embólicos ou complicações cirúrgicas. Na presença de metástases, o CCA
apresentava taxa de mortalidade de quase 100% e de aproximadamente 60% quando se
realizava histerectomia por doença aparentemente não metastática (Lurain, 2010). Atualmente,
mesmo com doença disseminada, a taxa de cura é superior a 90% (Braga et al., 2014; Goldstein
e Berkowitz, 2012; Kohorn, 2014; Lurain, 2010).
Estudo multicêntrico realizado no Brasil, observou que das 5.250 pacientes com
gestação molar estudadas, 21,8% evoluíram para NTG, sendo 81,3% classificadas como baixo
risco, 17,5% alto risco e 1,2% TTSP. Foi relatada taxa de cura global de 96,4%, com 0,4% de
óbitos em pacientes com doença de baixo risco, 9,5% nas de alto risco e 21,4% naquelas com
TTSP (Braga et al., 2014).
A NTG de baixo risco inclui doença não metastática (estadio I) e doença metastática
com escore FIGO/OMS inferior a 7 (Figo Oncology Committee, 2002; Goldstein e Berkowitz,
2012). Estas pacientes devem ser tratadas inicialmente com agente quimioterápico único, pelo
geral o MTX (Alazzam et al., 2012; Goldstein e Berkowitz, 2012; Maestá e Braga, 2012).
Para esse grupo de pacientes, a escolha da primeira linha de tratamento depende do
desejo de preservar a fertilidade. Para pacientes com prole constituída, pode-se oferecer HTA
associada a um ciclo QT por agente único adjuvante, com intuito de eliminar metástases ocultas
(Berkowitz e Goldstein, 2009).
Apesar da extensa experiência no tratamento da NTG de baixo risco acumulada ao longo
dos anos e da descrição de mais de 14 tipos diferentes de regimes quimioterápicos, não há
consenso acerca da primeira linha de tratamento. Na ausência de fortes evidências que
confirmem a superioridade de um método, diversos tratamentos são arbitrariamente utilizados
por diferentes centros (Alazzam et al., 2012; Berkowitz e Goldstein, 2013). No entanto, há
consenso sobre o uso de agente único, como MTX ou Act-D para essas pacientes (Lurain,
2011). São relatadas taxas de indução de remissão entre 50 e 90%, para essas duas drogas (Seckl
et al., 2013).
Três regimes são mais frequentemente utilizados: (1) MTX semanal intramuscular (IM)
em baixas doses; (2) Pulsos de Act-D endovenosa (EV) a cada 2 semanas; e (3) várias outras
dosagens de MTX com ou sem Ácido Folínico (FC) de resgate (Berkowitz e Goldstein, 2013).
22
A tabela 2 mostra as taxas de remissão primária de acordo com o regime de QT utilizado

(Lurain, 2011).
Tabela 2 – Taxas de remissão primária na Neoplasia Trofoblástica Gestacional de baixo risco

de acordo com o regime utilizado
Regime de QT Taxa de remissão
primária %
1) MTX 0,4mg/kg (máximo 25mg) /dia EV ou IM por 5d; repetir 87-93%
a cada 14 dias
2) MTX 30-50 mg/m2 IM semanalmente 49-74%
3) MTX 1mg/kg IM dias 1, 3, 5, 7; ácido folínico 0,1mg/kg IM 74-90%
dias 2,4,6,8; repetidos a cada 15-18 dias, ou quando necessário
4) MTX 100mg/m2 push EV, após 200mg/m2 em 500ml SG5% 69-90%
a cada 12h; ácido polínico 15mg IM ou VO 12/12h por 4 doses
começando 24h após o início do MTX; repetir a cada 18 dias ou
quando necessário
5) Act-D 10-13μg/kg EV diariamente por 5 dias; repetidos a 77-94%
cada 14 dias
6) Act-D 1,25 mg/m2 EV a cada 2 semanas 69-90%
7) Alternando regimes 1 e 5 (MTX/Act-D) 100%
A variabilidade na resposta primária reflete diferenças nas dosagens das drogas, horários
e vias de administração, bem como na seleção de pacientes. De um modo geral, injeção IM
semanal ou infusão EV intermitente de MTX e protocolos com Act-D a cada 2 semanas são
menos efetivos que protocolos com MTX e Act-D por 5 dias e MTX/FC por 8 dias. Porém,
apesar das diferentes taxas de remissão inicial com a QT primária, quase todas as pacientes são
curadas com preservação da fertilidade (Goldstein e Berkowitz, 2012; Lurain, 2011).
O regime com MTX 30-50mg/m2 semanal tem a vantagem da comodidade, baixo custo
e baixa toxicidade, porém apresenta a menor taxa de resposta completa quando comparado a
qualquer outro regime e não é terapia apropriada para doença metastática ou CCA (Lurain,
2011).
A Act-D tem sido utilizada como terapia primária quando há comprometimento renal
ou hepático ou contraindicações para uso do MTX e terapia secundária quando há resistência
ao MTX. Possui mais efeitos adversos (náuseas, alopecia) que o MTX e há risco de dano tissular
23
local caso haja extravasamento durante a aplicação EV. Os regimes mais eficazes são Act-D
10-12mcg/kg EV diariamente por 5 dias a cada duas semanas ou dose única de 1,25mg/m2 EV
a cada 2 semanas (Chapman-Davis et al., 2012; Lurain, 2011).
Diversos estudos têm comparado a eficácia de MTX versus Act-D para o tratamento da
NTG de baixo risco, a maioria retrospectivos e não randomizados. Um estudo randomizado
prospectivo recente do grupo Gynecologic Oncology Group mostrou que Act-D 1,25mg/m2 EV
a cada 2 semanas foi significativamente superior ao regime com MTX 30mg/m2 IM semanal,
com taxa de resposta completa de 70% versus 53% (p=0,01), respectivamente. Contudo, ambos
os regimes foram menos efetivos quando o escore era 5 ou 6 ou havia diagnóstico
histopatológico de CCA (Osborne et al., 2011).
Outros estudos também relataram taxas superiores de remissão primária com Act-D em
pulsos quando comparada a regimes com MTX semanal (Gilani et al., 2005; Yarandi et al.,
2008), MTX por 5 dias (Mousavi et al., 2012) e MTX/FC por 8 dias (Lertkhachonsuk et al.,
2009).
Atualização dos dados sobre tratamento da NTG no John I. Brewer Trophoblastic
Disease Center, em Chicago, com 359 pacientes tratadas entre 1979 e 2006, encontrou taxas de
remissão completa com agente único de 79% (78% com MTX e 86% com Act-D), com 92%
de resposta completa com terapia de agente único sequencial. Os 8% restantes alcançaram
remissão com agentes múltiplos e/ou cirurgia adjuvante (Hoekstra et al., 2008).
Estudo brasileiro comparou três regimes de QT para NTG de baixo risco; MTX por 5
dias, Act-D por 5 dias e combinação de MTX e Act-D (MACT) e encontrou taxas de remissão
primária de 69%, 71,4% e 79,1% respectivamente, diferenças não significativas. Efeitos
adversos foram significativamente mais frequentes no grupo MACT que naqueles tratados com
agente único. Os autores afirmam que regimes com agentes únicos são tão efetivos quanto à
combinação de drogas estudada e sugerem que Act-D é a droga menos tóxica e com melhor
custo e efetividade para o tratamento da NTG de baixo risco. No entanto, ressaltam que o MTX,
pela facilidade de administração, pode ser a primeira escolha em áreas com baixos recursos
(Abrão et al., 2008).
Independentemente do esquema de QT por agente único utilizado, a QT deve continuar
até que o hCG retorne aos valores normais e pelo menos mais três cursos de QT tenham sido
administrados após o primeiro hCG normal. A droga em uso deve ser substituída por outra,
caso seja observado platô de hCG ou instale-se toxicidade que não permita dose ou frequência
adequada de tratamento. Se houver elevação significativa de hCG, aparecimento de metástases
24
ou resistência sequencial aos agentes únicos, deve-se instituir QT por múltiplos agentes (Lurain,
2011).
Pelo que sabemos até o momento, qualquer regime de Act-D promove taxas de remissão
primária superior aos esquemas com MTX, porém, a maioria dos estudos comparam Act-D
quinzenal em pulso a MTX semanal, regime que tem sido visto como menos efetivo que aqueles
com 5 e 8 dias de tratamento (Alazzam et al., 2012).
Quanto aos efeitos adversos, a comparação entre os estudos é difícil frente à
heterogeneidade das pacientes envolvidas. Os efeitos adversos mais comuns para ambas as
drogas são náuseas, anemia e fadiga (Alazzam et al., 2012), semelhantes em ambos os regimes,
pulsado de Act-D e MTX em doses baixas. Porém, Lertkhachonsuk e colaboradores (2009)
relataram efeitos adversos mais graves, como alopecia e mucosite, no grupo que utilizou Act-
D. O estudo prospectivo GOG275 comparou esquemas de MTX em 5 ou 8 dias e Act-D,
concluindo que os esquemas são equivalentes em toxicidade, ainda que Act-D cause menos
mucosite oral e tenha mais conveniência posológica (Schink et al., 2020).
No momento, observa-se, pelo geral, que o tratamento da NTG de baixo risco é feito
com emprego do MTX. Trata-se de regime com mínimos efeitos colaterais, bem tolerado,
barato e com ótima resposta clínica.
1.3 Tratamento da NTG com quimiorresistência ao MTX
A despeito de 75-80% das pacientes com NTG tratadas com MTX alcançarem remissão,
20-25% delas vão cursar com quimiorresistência. Isso ocorre quando há platô ou aumento nos
níveis de hCG, com ou sem desenvolvimento de novas metástases, enquanto a paciente está
sendo tratado com MTX.
Aproximadamente 5% das pacientes com NTG de baixo risco sem metástases e 10-15%
daquelas com metástases desenvolverão resistência à QT primária (Lurain e Nejad, 2005). Para
doença de baixo risco, tratamento de resgate com outro regime de agente único (ex.: Act-D após
QT com MTX) usualmente é tudo que é preciso quando o hCG está em platô (El-Helw e
Hancock, 2007; Goldstein e Berkowitz, 2012). Quando há falha com a terapia sequencial com
agente único, deve-se instituir QT por múltiplos agentes, sendo EMA-CO o regime mais
comumente utilizado (Goldstein e Berkowitz, 2012).
Devido a questões mercadológicas, o Brasil vive desde 2013 um desabastecimento
periódico de Act-D, comprometendo o tratamento de pacientes com NTG resistente ao MTX.
Nesse período, não obstante pressões institucionais feitas pela Associação Brasileira de Doença
25
Trofoblástica Gestacional, pela Federação Brasileira das Associações de Ginecologia e

Obstetrícia e pela Sociedade Brasileira de Oncologia Clínica, no sentido de normalizar a
distribuição da Act-D, a falta desse medicamento levou os médicos brasileiros que tratam essa
neoplasia a buscar alternativas terapêuticas. Nesse contexto de falta da Act-D, foram
empregados dois quimioterápicos para tratamento de NTG resistente ao MTX: a Carboplatina
e o Etoposide.
A Carboplatina é um agente antineoplásico composto de platina. Em seu mecanismo de
ação, a Carboplatina se liga ao DNA celular por meio de ligações cruzadas nas duas cadeias,
alterando a configuração da hélice e inibindo sua síntese. O efeito é provavelmente
independente do ciclo. Baseado não apenas nos excelentes resultados da Carboplatina como
agente único no tratamento de seminomas (Bokemeyer et al., 2004; Horwich e Dearnaley, 1992;
Oliver et al., 2005), como também no tratamento de NTG como agente único (Winter et al.,
2016) ou em associação com múltiplos agentes (El-Helw et al., 2005; Lotz et al., 1995;
Piamsomboon et al., 1997; Rathod et al., 2015; van Besien et al., 1997; Yamamoto et al., 2016),
esse medicamento tem-se mostrado seguro e efetivo no tratamento de mulheres com neoplasias
germinativas ou trofoblásticas. No estudo de Winter e colaboradores (2016), os autores
apresentaram que mulheres com NTG resistente ao MTX cursaram com remissão em 81% após
o tratamento com Carboplatina. Relataram ainda os autores que o tratamento foi bem tolerado,
referindo alopecia não significativa, e apontando a mielossupressão como a toxicidade mais
significativa (um terço das pacientes apresentavam trombocitopenia / neutropenia graus 3 / 4).
O Etoposide é um agente antineoplásico, derivado semissintético da podofilotoxina. Seu
mecanismo de ação não é exatamente conhecido; no entanto, este fármaco parece produzir
efeitos citotóxicos que causam alterações do DNA celular, promovendo a suspensão da fase
G2, destruindo preferencialmente as células dessa fase e de fases S tardias, levando à inibição
da prófase celular e causando a lise das células em início de mitose, pela ruptura na fita única
do DNA. Desde a década de 1990 o Etoposide vem sendo utilizado isoladamente (Baptista e
Belfort, 2012; Chen et al., 2012; Hitchins et al., 1988; Matsui et al., 1998) ou em associação
com outros quimioterápicos (Alifrangis et al., 2013; Byun et al., 2016; Even et al., 2014;
Nevado-Gammad e Soriano-Estrella, 2016; Song et al., 2015) para o tratamento de pacientes
com NTG.
Felizmente, a despeito do esquema quimioterápico empregado, é a NTG uma das
neoplasias humanas mais amplamente curáveis, notadamente se as pacientes são tratadas em
Centro de Referência, por médicos experientes. Mesmo em casos de neoplasia multimetastática,
26
taxas de cura acima de 90% apontam para a necessidade do diagnóstico precoce como estratégia
de maximizar a cura dessas mulheres jovens.
Este estudo descreve os resultados do tratamento de pacientes brasileiras com NTG de
baixo risco resistente a MTX/AF com actinomicina-D, carboplatina ou etoposide e compara
nossa experiência com a literatura. É importante ressaltar que, em uma época em que os
mercados globais apresentam escassez frequente de quimioterápicos, é fundamental avaliar a
eficácia de tratamentos alternativos (Gatesman e Smith, 2011; McBride et al., 2013).
2. Objetivos do Estudo
Objetivo Principal: Comparar o desfecho clínico de mulheres com NTG de baixo risco
após resistência a metotrexato e ácido folínico (MTX/AF), tratadas alternativamente com
Actinomicina D (Act-D), Carboplatina ou Etoposide.
Objetivos Secundários:
● Avaliar a remissão laboratorial de NTG quimiorresistente ao MTX em mulheres
tratadas com Act-D, Carboplatina ou Etoposide.
● Estudar o impacto do tratamento de mulheres com Act-D, Carboplatina ou
Etoposide após o diagnóstico de NTG quimiorresistente ao MTX no que tange
ao tempo para remissão.
● Descrever a toxicidade do tratamento com Act-D, Carboplatina ou Etoposide
nesse cenário.
27
3. Material e Métodos
2.1 Desenho do Estudo
Este é um estudo de coorte retrospectivo colaborativo de pacientes com NTG

acompanhadas na Maternidade Escola da Universidade Federal do Rio de Janeiro (Rio de
Janeiro - RJ, Brasil), no Centro de Doenças Trofoblásticas do Hospital São Paulo da
Universidade Federal de São Paulo (São Paulo - SP, Brasil) e na Maternidade Mario Totta do
Hospital Irmandade da Santa Casa de Misericórdia (Porto Alegre - RS, Brasil), de janeiro de
2010 a dezembro de 2017.
Este estudo foi aprovado pelo Comitê de Ética em Pesquisa da Associação Brasileira de
Ética em Pesquisa da Maternidade Escola da Universidade Federal do Rio de Janeiro (CAAE
95188418.2.0000.5275), do Hospital São Paulo da Universidade Federal de São Paulo (CAAE
95188418.2.3003.5505) e da Maternidade Mario Totta na Irmandade da Santa Casa de
Misericórdia de Porto Alegre (CAAE 95188418.2.3001.5335).
2.2 Participantes do estudo
Foram incluídas neste estudo pacientes diagnosticadas com NTG de baixo risco, de
acordo com os critérios da FIGO 2000 (Figo Oncology Committee, 2002), com diagnóstico de
resistência a MTX/AF e subsequentemente tratadas com Act-D, carboplatina ou etoposide.
Todas as pacientes foram acompanhadas por, pelo menos, 12 meses após a remissão laboratorial
– normalização do hCG com a subsequente consolidação indicada. Todos os casos de gravidez
molar que desenvolveram NTG tiveram seu diagnóstico confirmado pelo Departamento de
Patologia dos Centros de Referência. Foram excluídas pacientes diagnosticadas com NTG dos
tipos tumor trofoblástico de localização placentária e tumor trofoblástico epitelioide de alto
risco, assim como pacientes tratadas com esquemas multiagentes como terapia de segunda linha
após o diagnóstico de resistência a MTX/AF. Pacientes que não puderam fazer o tratamento
com MTX/AF devido à toxicidade também foram excluídas deste estudo, para tornar os
resultados mais comparáveis aos de Winter e colaboradores (2016), que incluíram apenas
pacientes que desenvolveram resistência ao MTX/AF.
28
2.3 Amostragem
Na publicação de Winter e colaboradores (2016) a taxa de resposta completa à

carboplatina como agente único foi 17/21 pacientes (81%; intervalo de confiança de 95% 59%
-93%) e a taxa de resposta completa à actinomicina D foi 53/59 pacientes (90%; intervalo de
confiança de 95% 79% - 96%). Isso sugere que a diferença absoluta entre os dois regimes pode
chegar a 37%, dentro de uma faixa de incerteza aceitável. No relatório anterior, no entanto, as
pacientes receberam carboplatina ou actinomicina D de acordo com um algoritmo adaptado ao
risco. Pacientes com hCG <150 UI/L no primeiro período do estudo e hCG <300 UI/L no
segundo período do estudo receberam actinomicina D de agente único, enquanto pacientes com
hCG> 300 UI/L foram elegíveis para receber tratamento de segunda linha com carboplatina.
Isso deixa em aberto a questão de saber se a carboplatina não seria inferior à actinomicina D
em pacientes não selecionadas que necessitam de quimioterapia de segunda linha.
Como as taxas de resposta completas à actinomicina D na quimioterapia de segunda
linha para NTG de baixo risco e resistente ao metotrexato variam de 60% a 90% (Covens et al.,
2006; Uberti et al., 2015; Winter et al., 2016), realizamos nosso cálculo de potência tendo como
premissa uma taxa de resposta média de 80% a cada regime em segunda linha. Com base no
artigo de Winter e colaboradores (2016), postulamos de maneira conservadora a hipótese nula
de que os regimes sejam igualmente eficazes dentro de uma faixa absoluta de 30%. Para calcular
o poder estatístico do estudo, isso significa que, se não houver realmente diferença entre a
actinomicina D e a carboplatina, será necessário que 44 pacientes (pelo menos 22 em cada
grupo) tenham poder de 80% para garantir que o limite superior de um intervalo de confiança
unilateral de 95% (ou equivalente a um intervalo de confiança bilateral de 90%) excluiria uma
diferença absoluta nas taxas de cura em favor da actinomicina D superior a 30% (Blackwelder,
1982; Sealed Envelope | Power Calculator for Binary Outcome Non-Inferiority Trial, n.d.).
A oportunidade do estudo e comparação de carboplatina nesse cenário surgiram pela
escassez da actinomicina; assim, a amostra da coorte de carboplatina foi estabelecida pelos
critérios de inclusão e exclusão, e parametrizada pelo cálculo realizado com base nas hipóteses
a priori. Desta forma, as pacientes foram captadas a partir dos centros listados, buscando atingir
o número necessário ao poder do estudo –incluindo todas as pacientes do período citado, assim
configurando uma amostra de conveniência, ainda que o cálculo de amostra tenha sido
necessário para estabelecer a significância desejada (Vassar & Matthew, 2013; Worster &
Haines, 2004).
29
2.4 Diagnóstico de NTG
De acordo com os critérios da FIGO 2000, a NTG foi diagnosticada quando havia um
diagnóstico histológico de coriocarcinoma ou quando o monitoramento sérico quantitativo de
hCG exibiu quatro valores de platô de hCG por um período de pelo menos três semanas, um
nível aumentado de hCG em três medições consecutivas ou mais por pelo menos duas semanas,
ou quando os níveis de hCG permaneceram elevados, mesmo que estivessem caindo, seis meses
ou mais após a evacuação de uma gravidez molar (Figo Oncology Committee, 2002). Ainda
que esses critérios tenham sido modificados à luz de novas referências, durante o planejamento
e a coleta de dados mantivemos os critérios até então estabelecidos.
2.5 Estadiamento, Fatores de risco e Tratamento de NTG
As pacientes foram classificadas de acordo com o estadiamento anatômico FIGO 2000

NTG e a elas foi atribuído um escore prognóstico para resistência à quimioterapia de agente
único, seguindo o Sistema de Pontuação Prognóstica FIGO/OMS (Kang et al., 2010). As
metástases pulmonares foram detectadas por radiografia de tórax (Braga et al., 2018; Figo
Oncology Committee, 2002; Ngan et al., 2018). A ressonância magnética do cérebro e do
abdome foi utilizada em pacientes com metástase pulmonar visível na radiografia de tórax ou
metástase genital (Braga et al., 2018; Figo Oncology Committee, 2002; Ngan et al., 2018). A
indicação das ferramentas de diagnóstico no estadiamento de NTGs possui implicações
importantes para a classificação das pacientes. O uso de tomografias de tórax de forma
indiscriminada pode levar a super detecção de nódulos pulmonares que não são visualizados
em radiografias simples, não são considerados pela FIGO na sua determinação de escore e, mais
importante, não mudam o prognóstico quando detectados (Parker et al., 2021). Apesar disso,
para este grupo de pacientes estudado, já tratadas anteriormente com quimioterapia e em
avaliação para novo esquema de tratamento, os procedimentos radiológicos de estadiamento
foram importantes para a decisão clínica sobre o esquema a ser oferecido, uma vez que a
indisponibilidade ampla de actinomicina gerou a necessidade de adaptação das rotinas de
tratamento (Braga et al., 2021).
A medição de hCG em todos os Centros de Referência empregou o ensaio Immulite®
da Siemens Diagnostic Products Corporation (DPC). O valor de referência para resultados
normais era um valor de hCG abaixo de 5 UI/L. Todas as pacientes incluídas neste estudo
receberam aconselhamento contraceptivo e contracepção hormonal (Braga et al., 2018).
30
O regime de 8 dias de MTX/AF com metotrexato 1 mg / kg por via intramuscular nos

dias 1, 3, 5 e 7, alternando com ácido folínico 0,1 mg/kg por via oral nos dias 2, 4, 6 e 8, foi
usado como primeira linha de tratamento nos casos de NTG de baixo risco, se não houvesse
contraindicação (Braga et al., 2018; Figo Oncology Committee, 2002; Ngan et al., 2018). Nos
casos de resistência a MTX/AF e quando disponível, a quimioterapia de segunda linha foi
administrada com Act-D 1,25mg/m2 (máximo de 2,0mg) pulso endovenoso a cada 2 semanas
(Braga et al., 2018; Figo Oncology Committee, 2002; Ngan et al., 2018).
Em períodos de escassez de Act-D, as pacientes foram orientadas sobre as opções
terapêuticas disponíveis. Após o aconselhamento, a escolha do tratamento foi ditada pela
preferência da paciente/médico individualmente, sem randomização formal. As pacientes foram
tratadas com um dos regimes quimioterápicos listados a seguir:
a. Carboplatina AUC = 6 a cada 21 dias com dose máxima de 900 mg. A dose foi
calculada usando a fórmula de Calvert e a estimação GFR de Cockcroft-Gault, como descrito
por Winter e colaboradores (2016).
b. Etoposide, dose de 100mg/m2, dias 1-5, a cada 14 dias (Baptista e Belfort, 2012;
Matsui et al., 1998).
A partir de 2013, houve escassez e indisponibilidade de Act-D para tratar a NTG de
baixo risco resistente ao MTX no Brasil, e usamos o etoposide como terapia de segunda linha
em 2013-2014. Quando tomamos conhecimento, mesmo antes de sua publicação, dos
resultados favoráveis do tratamento de segunda linha com carboplatina no Sheffield Center for
Trophoblastic Disease, mudamos para a carboplatina em 2015-2017.
O tratamento era adiado, caso a paciente apresentasse neutropenia (<1.000 / mm3) ou
trombocitopenia (<75.000 / mm3), até a recuperação, e a dose de carboplatina era reduzida para
uma AUC estimada de 5 mg/mL/min para doses subsequentes (Winter et al., 2016). Caso a
toxicidade hematológica (leucopenia ou neutropenia) causasse pelo menos um atraso nos ciclos
de quimioterapia, o fator estimulador de colônias de granulócitos era rotineiramente usado nos
ciclos subsequentes, até a remissão da doença.
Na ocorrência de resistência à terapia de segunda linha, toxicidade grave (grau 3 ou 4
em dois ciclos consecutivos) no tratamento de segunda linha ou desejo da paciente após
orientação médica após o primeiro episódio de toxicidade de grau 3 ou 4 na segunda linha, uma
terceira linha de etoposide, MTX/AF, ciclofosfamida e Oncovin® (vincristina) (EM/CO) era
administrada, ou seja, o protocolo EMA/CO sem Act-D, enquanto paclitaxel, cisplatina e
etoposide (TP/TE) foram utilizados como regime de quarta linha.
Após a normalização do hCG, as pacientes receberam 3 ciclos da consolidação de
31
quimioterapia, que foi interrompida em caso de toxicidade, e foram monitoradas mensalmente

com níveis do hCG por 12 meses, quando receberam alta do seguimento (Braga et al., 2018).
Se as pacientes não comparecessem às visitas agendadas, um assistente social e um psicólogo
do hospital tentavam entrar em contato com as pacientes ativamente por telefone, mensagem
eletrônica e telegrama para identificar o que estava impedindo a conformidade e para motivá-
las a voltar ao acompanhamento.
2.6 Desfechos
O desfecho primário foi a ocorrência de remissão após quimioterapia em segunda linha

(Act-D, carboplatina ou etoposide). Os desfechos secundários foram toxicidade nos vários
regimes de quimioterapia de segunda linha, número de ciclos necessários para atingir a remissão
de NTG, tempo para remissão, duração do acompanhamento e ocorrência de recidiva e
morte.
32
2.7 Variáveis
Foram estudadas as seguintes variáveis populacionais: idade (em anos), número de

gestações e paridade da paciente.
Foram avaliadas as seguintes variáveis clínicas da doença trofoblástica gestacional:
idade gestacional no diagnóstico (em semanas), ocorrência de complicações médicas no
momento do diagnóstico: anemia (hemoglobina menor que 9 g/dL), sangramento vaginal, útero
aumentado para a idade gestacional (quando o tamanho uterino é mais de 4 centímetros acima
do esperado para a altura do fundo para a idade gestacional), cistos de teca luteína (presença de
cisto ovariano superior a 6 centímetros), pré-eclâmpsia (níveis de pressão arterial sistólica
acima de 140 mmHg ou diastólica acima de 90 mmHg com proteinúria maior que 300 mg/24h),
hiperêmese (mais de 5 episódios de vômito por dia, com ou sem alterações metabólicas),
hipertireoidismo (níveis de hormônio estimulador da tireoide abaixo de 0,01 UI/L e tiroxina
livre acima de 91,5 ng/dL) e insuficiência respiratória.
As seguintes variáveis patológicas foram avaliadas: o diagnóstico histopatológico de
doença trofoblástica gestacional (mola hidatiforme completa ou parcial ou coriocarcinoma) e o
nível de hCG no diagnóstico de doença trofoblástica gestacional (UI/L).
Em relação aos aspectos clínicos da neoplasia trofoblástica gestacional, foram
estudadas as seguintes variáveis: estágio NTG e escore prognóstico FIGO/OMS, gravidez
antecedente (gravidez molar, gravidez a termo/pré-termo, aborto ou gravidez ectópica), nível
de pré-tratamento com hCG (UI/L) e tempo entre o final da gravidez antecedente e o início da
quimioterapia com MTX/AF.
Considerando as variáveis terapêuticas da NTG, avaliamos o número de ciclos de
MTX/AF administrados, o tempo necessário para mudar para o tratamento de segunda linha
(em semanas), o nível de hCG no momento da resistência a MTX/AF (UI/L), número de ciclos
de quimioterapia de segunda linha (sem ciclos de consolidação), tipo e intensidade de
toxicidade da quimioterapia de segunda linha, excluindo episódios após remissão durante a
quimioterapia de consolidação, de acordo com os Critérios comuns de terminologia para
eventos adversos, versão 5.0, 2017 (Common Terminology Criteria for Adverse Events
(CTCAE) | Protocol Development | CTEP, 2017), ocorrência de atraso e número de dias de
atraso para iniciar um novo ciclo de quimioterapia devido à toxicidade, ocorrência de remissão
com o regime de segunda linha (definido como normalização dos níveis de hCG - inferior a 5
UI/L - que foi mantida por pelo menos 3 semanas), resistência ao regime de segunda linha
(caracterizado por platô de hCG de ± 10% após 2 ciclos de quimioterapia ou sua reelevação),
33
toxicidade como motivo para mudar para um regime em terceira linha (caracterizada pela
ocorrência de toxicidade de grau 3 ou 4 em dois ciclos consecutivos, ou pelo desejo da paciente
após orientação médica, após o primeiro episódio de toxicidade de grau 3 ou 4 no regime de
segunda linha), recidiva (caracterizada pela reelevação de níveis de hCG após remissão, na
ausência de uma nova gravidez) e morte.
2.8 Análise estatística
Para analisar a associação entre os tratamentos quimioterápicos de segunda linha (Act-

D, carboplatina ou etoposide) e cada uma das variáveis categóricas, foram utilizados os testes
qui-quadrado ou o teste exato de Fisher, quando apropriado.
O teste de Kruskal-Wallis foi utilizado para comparar variáveis contínuas entre os
tratamentos quimioterápicos de segunda linha. Um teste U de Mann-Whitney, corrigido por
Bonferroni, foi usado para comparações pareadas entre dois grupos em casos de significância
pelo teste de Kruskal-Wallis.
As diferenças foram consideradas estatisticamente significantes quando os valores de p
foram menores que 0,05. A análise estatística foi realizada usando o programa IBM SPSS® para
Windows versão 18.0 e o ambiente R versão 3.3.2, disponível em www.r-project.org .
34
4. Resultados
A Figura 1 representa um fluxograma descrevendo a população do estudo. De janeiro

de 2010 a dezembro de 2017, 2.158 pacientes foram diagnosticadas com doença trofoblástica
gestacional (DTG). Entre elas, 1.737 (80,5%) alcançaram remissão espontânea e 421 (19,5%)
desenvolveram NTG, dentre as quais 377 (89,5%) foram categorizadas como NTG de baixo
risco e 356 (94,4%) foram tratadas com agente único MTX/AF. Das 356 pacientes com NTG
de baixo risco tratadas com MTX/AF, 75 (21,1%) desenvolveram resistência, das quais 40
(53,3%) receberam Act-D, 23 (30,7%), carboplatina e 7 (9,3%) etoposide.
A apresentação inicial das pacientes com NTG de baixo risco com resistência a
MTX/AF foi semelhante entre os três regimes estudados (Tabela 3). Os diferentes grupos de
pacientes tratadas foram comparáveis, sem diferenças estatísticas em idade (p = 0,982),
gravidade (p = 0,902), paridade (p = 0,601), idade gestacional no diagnóstico (p = 0,872),
ocorrência de complicações médicas, histologia da DTG (p = 0,768), ou pré-evacuação do
nível de hCG (p = 0,126).
35
Figura 1. Diagrama resumindo a divisão da população do estudo.

36
Tabela 3. Características de pacientes com neoplasia trofoblástica gestacional de baixo

risco resistentes ao MTX/AF, de acordo com o esquema de segunda linha.
# Mediana e intervalo interquartil.

* DTG – doença Trofoblástica gestacional.
** hCG – human chorionic gonadotropin (IU/L – International units per liter) – Gonadotrofina coriônica humana
C – Teste de Qui Quadrado.
K – Teste de Kruskal-Wallis.
Pacientes com resistência ao MTX/AF tratadas com Act-D, carboplatina ou etoposide

da mesma forma não diferiram nos aspectos clínicos e terapêuticos do manejo de NTG de
baixo risco (Tabela 4). Eram principalmente pacientes com NTG não metastático (p = 0,952)
após gestações molares (p = 0,456), com baixos escores de risco prognóstico da OMS/FIGO
(p = 0,818) e valores de hCG moderadamente elevados ao iniciar a terapia primária (p = 0,989).
A maioria das pacientes iniciou quimioterapia dentro de 4 meses após o término da gravidez
(p = 0,729) e experimentou resistência após cerca de 5 ciclos (p = 0,785). Os níveis de hCG
foram semelhantes entre os três grupos no momento da mudança para um regime de segunda
linha: 7.890, 1.385 e 4250 UI / L (p = 0,188), respectivamente.
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Tabela 4. Perfil clínico e terapêutico de pacientes com falha ao MTX/AF para o
tratamento de neoplasia trofoblástica gestacional de baixo risco, de acordo com o esquema
de tratamento de segunda linha.

* WHO/FIGO – World Health Organization / International Federation of Gynecology and Obstetrics. OMS/FIGO
– Organização Mundial da Saúde / Federação Internacional de Ginecologia e Obstetrícia
(IU/L – Unidades Internacionais por litro).
*** MTX/AF – Metotrexate com resgate com ácido folínico.
K – Teste de Kruskal-Wallis.
38
As taxas de remissão entre os três regimes de segunda linha, Act-D (80%) e etoposide
(71,4%, p = 0,659) foram semelhantes, mas ambas foram superiores à carboplatina (47,8%, p
= 0,033 e p = 0,025, respectivamente) (Tabela 5). O número de ciclos necessários para alcançar
a remissão foi significativamente diferente entre os grupos estudados (p = 0,002): são
necessários mais ciclos de Act-D em comparação à carboplatina (p = 0,016) ou ao etoposide
(p = 0,027), enquanto não houve diferença entre o número de ciclos de carboplatina e etoposide
necessários para induzir a remissão (p = 0,479). O número total de ciclos administrados de
Act-D, carboplatina e etoposide foi 203, 56 e 23, respectivamente. Houve um aumento
significativo na ocorrência de quimiorresistência/toxicidade entre as pacientes tratadas com
carboplatina (52,2%) comparado às pacientes que receberam Act-D (20%, p = 0,008) ou
etoposide (28,5%, p = 0,022).
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Tabela 5. Desfechos dos esquemas de tratamento de segunda linha de pacientes com

neoplasia trofoblástica gestacional de baixo risco, após a falha a MTX/AF.
S
Sem incluir a consolidação.
* IC – Intervalo de confiança.
(IU/L – Unidades Internacionais por litro)
*** G-CSF – Granulocyte-colony stimulating factor – Fator de estimulação de colônias de granulócitos.
K – Teste de Kruskal-Wallis.F – Teste exato de Fisher.
M – Teste de Mann-Whitney com Correção de Bonferroni.
Também foi observado que apenas 29% das pacientes tratadas com carboplatina
receberam os ciclos de quimioterapia sem atraso, o que foi significativamente diferente quando
comparado às mulheres tratadas com Act-D (98%, p <0,001) ou etoposide (85%, p = 0,009).
Entre as pacientes tratadas com Act-D, 5 (2,4%) ciclos necessitaram de atraso, enquanto entre
as pacientes tratadas com carboplatina e etoposide isso ocorreu em 39 (69,6%) e 4 (17,4%)
ciclos, respectivamente. O tempo de atraso foi significativamente maior nas pacientes tratadas
com carboplatina (mediana de 8 dias, p = 0,001) ou etoposide (mediana de 5 dias, p = 0,051),
quando comparado àquelas tratadas com Act-D (mediana de 4 dias).
Os atrasos significativos entre os ciclos de carboplatina ocorreram devido à toxicidade
do tratamento. A Tabela 6 mostra que apenas as pacientes tratadas com carboplatina
apresentaram toxicidade de grau 3 ou 4. As pacientes tratadas com carboplatina apresentaram
significativamente mais toxicidade hematológica, especialmente anemia (30,4%, p = 0,008),
linfopenia (47,7%, p <0,001) e trombocitopenia (43,4%, p <0,001), além de maior ocorrência
de neutropenia febril (14,4%, p = 0,044) e vômitos (60%, p <0,001), do que aquelas que
receberam Act-D (5%, nenhum, 2,5%, nenhum, 10%, respectivamente). Alopecia foi relatada
de maneira significativa entre as pacientes tratadas com etoposide (100%, p <0,001), sendo
incomum entre as pacientes tratadas com Act-D (5%) ou carboplatina (4,3%). Devido à
40
toxicidade, 27 (48,2%) ciclos de carboplatina foram administrados na redução de dose de

AUC5.
Comparado às pacientes tratadas com Act-D, o número de mulheres tratadas com
carboplatina (39%, p <0,001) ou etoposide (29%, p = 0,019) que necessitaram de tratamento
com G-CSF foi significativamente maior (Tabela 5). Todas as pacientes que não responderam
ao regime de segunda linha foram tratadas com sucesso com quimioterapia de múltiplos
agentes, como mostrado na Figura 1, e não houve casos de recidiva ou morte entre as pacientes
estudadas.
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Tabela 6. Eventos adversos secundários ao regime de segunda linha para o tratamento de
neoplasia trofoblástica gestacional de baixo risco, após a resistência ao metotrexato/ácido
folínico, graduado de acordo com o Critério Comum de Toxicidade (CTC) para Eventos
Adversos, versão 5.0 (2017).
TGP – transaminase glutâmico pirúvica/alanina aminotrasnferase (ALT)

TGO – transaminase glutâmico oxaloacética/aspartato aminotransferase (AST)
G-CSF – Granulocyte-colony stimulating factor – Fator de estimulação de colônias de granulócitos.
NR – Não reportado.
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5. Discussão
Embora a maioria das pacientes com NTG de baixo risco alcancem remissão com
quimioterapia de agente único (Seckl et al., 2013), nosso estudo mostrou que 21% das
pacientes precisavam de um regime de segunda linha, semelhante aos estudos anteriores (Kang
et al., 2010; Lurain, 2011; Prouvot et al., 2018; Seckl et al., 2013; Uberti et al., 2015). Mesmo
que não haja consenso a respeito do melhor tratamento de segunda linha para NTG (Ngan et
al., 2018), a expectativa é que a maioria das mulheres ainda possa ser curada com uma
quimioterapia de segunda linha com agente único, evitando assim o tratamento com múltiplos
agentes e suas toxicidades iniciais e tardias (Lurain, 2011; Ngan et al., 2018; Prouvot et al.,
2018).
Há uma base sólida para o uso de agentes anti PDL1 em NTG, dada sua elevada
expressão nos tecidos trofoblásticos (Keir et al., 2008). As experiências iniciais bem sucedidas
com imunoterapia anti PDL1 em pacientes com NTG politratadas ou refratárias migraram para
testes em linhas mais precoces (Clair et al., 2020; Paspalj et al., 2021). Recentemente uma das
coortes de fase II do estudo TROPHOIMMUN foi publicada, onde pacientes de baixo risco e
que apresentavam resistência ao metotrexato foram tratadas com avelumabe e alcançaram
53,3% de remissão, com toxicidades possivelmente menores do que as alternativas
convencionais de quimioterapia, e certamente menores do que as opções de poliquimioterapia
(You et al., 2020). Seguindo a mesma tendência de outras neoplasias sólidas, também a
combinação de antiangiogênicos e anti PDL1 foi testada em pacientes com NTG
quimiorefratária, com remissão alcançada em 50% das pacientes tratadas (Cheng et al., 2021).
Mesmo que consideremos o benefício de se explorar e obter uma estratégia de cura sem uso
de quimioterápicos citotóxicos e seus indesejados paraefeitos, os custos envolvidos e as taxas
de remissão completa ainda não posicionam essa linha de tratamento além do campo
experimental nos cenários de tratamentos iniciais de baixo risco. Por outro lado, a
consolidação dos dados positivos sobre o uso de imunoterápicos em cenários mais graves é
aguardada para os casos onde a resistência à quimioterapia pode levar jovens pacientes ao
óbito inevitável por progressão da doença (Braga et al., 2021).
Neste estudo, demonstramos que a carboplatina apresentou uma taxa de remissão
menor que a Act-D e o etoposide como regime de segunda linha para NTG de baixo risco após
resistência ao MTX/AF. A carboplatina apresentou maior ocorrência de falha na quimioterapia
e maior taxa de toxicidade de grau 3 ou 4, relacionadas ao comprometimento hematológico.
Embora as pacientes que receberam carboplatina precisassem de mais apoio com G-CSF do
43
que aquelas tratadas com Act-D, mais de dois terços das pacientes em carboplatina sofreram
atrasos nos ciclos de quimioterapia, adiando a continuidade do tratamento quando comparado
às pacientes tratadas com Act-D.
Apesar do tempo de inclusão e a não concorrência das coortes, tal período não
apresentou mudança de tecnologia ou incorporação terapêutica relevante para a mudança de
prognóstico das NTGs; desta forma, a linha de tempo de inclusão não possui elementos que
nos levem a crer em um efeito coorte neste estudo (Keyes et al., 2010).
O único estudo anterior que avaliou a resposta ao tratamento de segunda linha de
pacientes com NTG de baixo risco após resistência ao MTX/AF encontrou taxas de remissão
semelhantes em mulheres tratadas com Act-D e carboplatina (53/59 - 89,8% versus 17/21 -
80,9 %, respectivamente) (Winter et al., 2016), taxas mais altas do que as observadas em nosso
estudo (Tabela 7). Características populacionais, como raça e etnia, foram citadas para explicar
diferentes respostas e toxicidade aos tratamentos quimioterápicos com carboplatina e outros
agentes (Katsumata et al., 2009; Marchetti et al., 2018). É possível que diferenças na
população de pacientes possam explicar parcialmente as diferenças nos resultados entre a
experiência com Winter e colaboradores (2016) e nossos dados. No mesmo estudo, nota-se
que os níveis de hCG no momento da mudança para a terapia de segunda linha apresentaram
níveis medianos e interquartis mais baixos entre as pacientes que foram tratadas com Act-D
do que entre as mulheres que foram tratadas com carboplatina (28, interquartil: 18-69 UI/L
versus 2126, interquartil: 1149-7948 UI/L, respectivamente). Em nosso estudo, pacientes com
NTG de baixo risco após resistência ao MTX/AF, tratadas com diferentes esquemas de
segunda linha, foram comparáveis em variáveis comumente associadas à resposta à
quimioterapia, como idade, nível de hCG na data em que não responderam à quimioterapia de
primeira linha, histologia do DTG, gravidez antecedente, intervalo entre o final da gravidez
anterior e o início da quimioterapia MTX/AF, presença de doença metastática e escore
FIGO/OMS (Lurain et al., 2010; Prouvot et al., 2018; Strohl e Lurain, 2016).
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Tabela 7. Comparação Indireta de Dados entre os Estudos de Carboplatina em Segunda

Linha para NTG Resistente ao MTX.
Variável Brasil Sheffield

Resposta à Carboplatina 47,8% 80,9%
Idade (mediana) 25 anos 30 anos
Níveis de hCG Similares entre os grupos Menores para Act-D
Neutropenia (carboplatina) 56,5% 38,1%
Trombocitopenia (carboplatina) 43,4% 28,6%
Atraso no ciclo subsequente 71% 71,4%
Tempo mediano de atraso 8 dias NR
hCG – human chorionic gonadotropin – Gonadotrofina coriônica humana

NR – Não reportado
Em nossa casuística, houve maior ocorrência de quimiorresistência/toxicidade entre as

mulheres que receberam carboplatina. Winter e colaboradores (2016) relataram uma
toxicidade grau 3 ou 4 de neutropenia (38,1%) e trombocitopenia (28,6%), semelhante aos
nossos resultados, que identificaram a supressão da medula óssea como a principal toxicidade
entre as pacientes tratadas com carboplatina. Isso causou um atraso em 71,4% das pacientes
que receberam carboplatina, idêntico aos nossos resultados. No entanto, embora Winter e
colaboradores (2016) não tenham relatado o tempo necessário para reiniciar a quimioterapia,
este foi significativamente maior entre nossas pacientes tratadas com carboplatina (mediana
de 8 dias). O atraso entre os ciclos de carboplatina devido à toxicidade pode ter contribuído
para o aumento das taxas de resistência observadas entre essas pacientes (May et al., 2011).
Concordamos com Winter e colaboradores (2016) que as doses de carboplatina podem
estar superestimadas em 30% por conta de uma possível superestimação de clearance renal,
usando a fórmula Cockcroft-Gault baseada na creatinina sérica, e isso poderia estar
relacionado com os efeitos tóxicos observados. Do mesmo modo, pode ser necessário
considerar o uso profilático de G-CSF nas pacientes que precisam de carboplatina, ou iniciar
seu uso de forma precoce para evitar atraso nos ciclos e possível resistência à quimioterapia
com esse regime.
Embora tenha atingido excelentes taxas de remissão em pacientes com NTG de baixo
risco após resistência ao MTX/AF, com resultados semelhantes às pacientes tratadas com Act-
45
D e com menos ciclos de quimioterapia, o etoposide mostrou-se mais tóxico, apresentando

mais alopecia e neutropenia. O uso de etoposide também está associado ao risco de neoplasias
secundárias, incluindo leucemia, câncer de mama e de cólon e melanoma (Savage et al., 2015).
Nosso estudo tem várias limitações. A principal limitação sendo o pequeno número de
pacientes com resistência ao MTX/AF como terapia de primeira linha na NTG de baixo risco.
Apenas 21% das pacientes com NTG de baixo risco desenvolveram resistência ao MTX/AF.
Subdividir uma coorte tão pequena em diferentes grupos produz intervalos de confiança
amplos nas estimativas das taxas de resposta. Isso se aplica especialmente à avaliação do
etoposide. No entanto, embora considerássemos que as diferenças entre este estudo e o
relatório de Sheffield poderiam estar dentro da faixa de variação estatística, ainda assim, a
diferença absoluta nas taxas de resposta entre carboplatina e Act-D excedeu nossos critérios
muito conservadores por presumir eficácia equivalente, sugerindo ser improvável que somente
o tamanho da amostragem seja a fonte da variação. Os dados também foram coletados em
diferentes bancos de dados hospitalares e podem não refletir a população brasileira em geral.
Como centros de referência, esses dados podem superestimar a verdadeira prevalência de
resistência ao MTX/AF, atraindo pacientes com pior prognóstico para responder ao tratamento
com quimioterapia de agente único. Devido à natureza retrospectiva deste estudo, é importante
destacar que os eventos adversos para os diferentes esquemas foram identificados por meio da
revisão de prontuários, e não em tempo real, o que poderia introduzir viés de apuração ou ser
incompleto. Embora critérios bem estabelecidos tenham sido seguidos ao interromper um
regime quimioterápico por conta de toxicidade, os padrões de prática clínica e as pacientes
também podem influenciar essa decisão e, portanto, também podem explicar as diferenças
entre Winter e colaboradores (2016) e nossos resultados. Apesar dessas limitações, até onde
sabemos, esta é a maior casuística de pacientes com NTG de baixo risco após resistência ao
MTX/AF tratadas com carboplatina como segunda linha. Ao avaliar a taxa de resposta de
diferentes regimes de segunda linha em populações com perfil comparável, este estudo
apresenta uma importante contribuição à literatura sobre o papel potencial da carboplatina no
tratamento de mulheres brasileiras após falha de MTX/AF de primeira linha no tratamento de
NTG de baixo risco.
Nossos resultados reforçam a preferência pela Act-D como agente de segunda linha
em pacientes com NTG de baixo risco após resistência ao MTX/AF (Ngan et al., 2018; Prouvot
et al., 2018), não apenas porque a Act-D alcançou uma excelente taxa de resposta clínica, mas
também pela boa tolerabilidade, com poucos efeitos adversos. Embora seja crítico avaliar
alternativas terapêuticas em um mercado global que frequentemente sofre com a escassez de
46
medicamentos oncológicos, devemos estar cientes de que as alternativas propostas podem ser
não apenas mais caras, mas também mais tóxicas e não necessariamente tão eficazes
(Gatesman e Smith, 2011; McBride et al., 2013). Este trabalho também reforça que os regimes
de tratamento eficazes em uma população podem não ter resultados semelhantes quando
estudados em um país diferente, com composição racial/étnica diferenciada (Katsumata et al.,
2009; Marchetti et al., 2018). Embora não seja o objetivo deste estudo, devemos destacar que
a escassez de Act-D compromete não apenas o tratamento de mulheres com falha no
tratamento de primeira linha com MTX/AF para NTG de baixo risco, mas afeta diretamente o
tratamento de pacientes que não respondem ao tratamento de segunda linha e precisam de
regime multiagente, como EMA-CO (Ngan et al., 2018; Seckl et al., 2013).
47
6. Conclusões
Como medicamento quimioterápico utilizado no tratamento de mulheres brasileiras

com NTG de baixo risco após resistência ao MTX/AF devido à falta de Act-D, a carboplatina
não apresentou taxa de resposta clínica satisfatória, provavelmente por causa de efeitos
adversos hematológicos graves, que postergaram ciclos de quimioterapia. As pacientes
tratadas com Act-D tiveram uma excelente resposta clínica, sem os efeitos colaterais
observados com carboplatina e etoposide. Ainda assim, a carboplatina segue sendo utilizada
nacionalmente como alternativa nesse cenário, considerando sua ampla disponibilidade, perfil
clínico conhecido e falta de outra alternativa medicamentosa com essas características.
Na ausência de evidências mais robustas para definir o melhor tratamento para
mulheres com NTG de baixo risco após resistência ao MTX/AF, a Act-D segue como elemento
essencial para a linha de cuidado de NTG (Ministério da Saúde, 2021 versão preliminar). É
imprescindível que as organizações médicas governamentais e profissionais usem toda a sua
influência para reduzir a ocorrência de escassez global de agentes quimioterápicos que salvam
vidas (Braga et al., 2021).
48
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Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology:
Official Journal of the European Society for Medical Oncology, 24 Suppl 6(suppl 6),
vi39-50. https://doi.org/10.1093/annonc/mdt345
72. Song, S. Q., Wang, C., Zhang, G. N., Shi, Y., Zhu, Y., Hu, T., Xu, S. Q., & Yang, Z. R.
(2015). BEP for high-risk gestational trophoblastic tumor: Results from a cohort of 45
patients. European Journal of Gynaecological Oncology, 36(6), 726–729.
https://doi.org/10.12892/ejgo2707.2015
73. Soper, J. T., Mutch, D. G., & Schink, J. C. (2004). Diagnosis and treatment of
gestational trophoblastic disease: ACOG Practice Bulletin No. 53. Gynecologic
Oncology, 93(3), 575–585. https://doi.org/10.1016/j.ygyno.2004.05.013
57
74. Strohl, A. E., & Lurain, J. R. (2016). Postmolar choriocarcinoma: An independent risk
factor for chemotherapy resistance in low-risk gestational trophoblastic neoplasia.
Gynecologic Oncology, 141(2), 276–280. https://doi.org/10.1016/j.ygyno.2016.02.014
75. Sung, W. J., Shin, H. C., Kim, M. K., & Kim, M. J. (2013). Epithelioid trophoblastic
tumor: Clinicopathologic and immunohistochemical analysis of three cases. Korean
Journal of Pathology, 47(1), 67–73.
https://doi.org/10.4132/KoreanJPathol.2013.47.1.67
76. Uberti, E. M. H., Fajardo, M. do C., Cunha, A. G. V. da, Frota, S. S., Braga, A., & Ayub,
A. C. K. (2015). Treatment of low-risk gestational trophoblastic neoplasia comparing
biweekly eight-day Methotrexate with folinic acid versus bolus-dose Actinomycin-D,
among Brazilian women. Revista Brasileira de Ginecologia e Obstetrícia.
https://doi.org/10.1590/SO100-720320150005366
77. van Besien, K., Verschraegen, C., Mehra, R., Giralt, S., Kudelka, A. P., Edwards, C. L.,
Piamsonboom, S., Termrungruanglert, W., Champlin, R., & Kavanagh, J. J. (1997).
Complete Remission of Refractory Gestational Trophoblastic Disease with Brain
Metastases Treated with Multicycle Ifosfamide, Carboplatin, and Etoposide (ICE) and
Stem Cell Rescue. Gynecologic Oncology, 65(2), 366–369.
https://doi.org/10.1006/gyno.1997.4677
78. Vassar, M., & Matthew, H. (2013). The retrospective chart review: important
methodological considerations. Journal of Educational Evaluation for Health
Professions, 10, 12. https://doi.org/10.3352/jeehp.2013.10.12
79. Vassar, M., & Matthew, H. (2013). The retrospective chart review: important
methodological considerations. Journal of Educational Evaluation for Health
Professions, 10, 12. https://doi.org/10.3352/jeehp.2013.10.12
80. Winter, M. C., Tidy, J. A., Hills, A., Ireson, J., Gillett, S., Singh, K., Hancock, B. W.,
& Coleman, R. E. (2016). Risk adapted single-agent dactinomycin or carboplatin for
second-line treatment of methotrexate resistant low-risk gestational trophoblastic
neoplasia. Gynecologic Oncology, 143(3), 565–570.
81. Worster, A., & Haines, T. (2004). Advanced statistics: Understanding Medical Record
Review (MRR) Studies. Academic Emergency Medicine, 11(2), 187–192.
https://doi.org/10.1111/J.1553-2712.2004.TB01433.X/FORMAT/PDF
58
82. Worster, A., & Haines, T. (2004). Advanced statistics: Understanding Medical Record
Review (MRR) Studies. Academic Emergency Medicine, 11(2), 187–192.
https://doi.org/10.1111/J.1553-2712.2004.TB01433.X/FORMAT/PDF
83. Yamamoto, E., Niimi, K., Fujikake, K., Nishida, T., Murata, M., Mitsuma, A., Ando,
Y., & Kikkawa, F. (2016). High-dose chemotherapy with autologous peripheral blood
stem cell transplantation for choriocarcinoma: A case report and literature review.
Molecular and Clinical Oncology, 5(5), 660–664.
https://doi.org/10.3892/mco.2016.1011
84. Yarandi, F., Eftekhar, Z., Shojaei, H., Kanani, S., Sharifi, A., & Hanjani, P. (2008).
Pulse methotrexate versus pulse actinomycin D in the treatment of low-risk gestational
trophoblastic neoplasia. International Journal of Gynecology and Obstetrics, 103(1),
33–37. https://doi.org/10.1016/j.ijgo.2008.05.013
85. You, B., Bolze, P. A., Lotz, J. P., Massardier, J., Gladieff, L., Joly, F., … Golfier, F.
(2020). Avelumab in Patients With Gestational Trophoblastic Tumors With Resistance
to Single-Agent Chemotherapy: Cohort A of the TROPHIMMUN Phase II Trial.
Journal of Clinical Oncology: Official Journal of the American Society of Clinical
Oncology, 38(27), 3129–3137. https://doi.org/10.1200/JCO.20.00803
86. You, B., Bolze, P. A., Lotz, J. P., Massardier, J., Gladieff, L., Joly, F., … Golfier, F.
(2020). Avelumab in Patients With Gestational Trophoblastic Tumors With Resistance
to Single-Agent Chemotherapy: Cohort A of the TROPHIMMUN Phase II Trial.
Journal of Clinical Oncology: Official Journal of the American Society of Clinical
Oncology, 38(27), 3129–3137. https://doi.org/10.1200/JCO.20.00803
59
7. Anexos
Anexo A. Aprovação dos Comitês de Ética
1. Comitê de Ética em Pesquisa da Associação Brasileira de Ética em Pesquisa da

Maternidade Escola da Universidade Federal do Rio de Janeiro (CAAE
95188418.2.0000.5275)
2. Hospital São Paulo da Universidade Federal de São Paulo (CAAE
95188418.2.3003.5505)
3. Maternidade Mario Totta na Irmandade da Santa Casa de Misericórdia de Porto Alegre
(CAAE 95188418.2.3001.5335).
UFRJ - MATERNIDADE
ESCOLA DA UNIVERSIDADE
FEDERAL DO RIO DE JANEIRO
PARECER CONSUBSTANCIADO DO CEP
DADOS DO PROJETO DE PESQUISA
Título da Pesquisa: Avaliação do tratamento da neoplasia trofoblástica gestacional resistente ao

Methotrexate
Pesquisador: Antônio Rodrigues Braga Neto
Área Temática: Reprodução Humana (pesquisas que se ocupam com o funcionamento do aparelho
reprodutor, procriação e fatores que afetam a saúde reprodutiva de humanos, sendo que
nessas pesquisas serão considerados "participantes da pesquisa" todos os que forem
afetados pelos procedimentos delas):
(Reprodução Humana que não necessita de análise ética por parte da CONEP;);
Versão: 1
CAAE: 95188418.2.0000.5275
Instituição Proponente: Maternidade Escola da Universidade Federal do Rio de Janeiro
Patrocinador Principal: Financiamento Próprio
DADOS DO PARECER
Número do Parecer: 2.852.096
Apresentação do Projeto:
O projeto “ Avaliação do tratamento da neoplasia trofoblástica gestacional resistente ao Methotrexate” trata-
se de estudo observacional, retrospectivo, colaborativo, de coortes não concorrentes, que avaliará
prontuários médicos de pacientes com diagnóstico de NTG quimiorresistente ao MTX, acompanhadas no
período de 01 de janeiro de 2007 até 31 de dezembro de 2017, tratadas com Act-D, Etoposide ou
Carboplatina.
Neoplasia trofoblástica gestacional (NTG) é o termo utilizado para designar lesões malignas que se originam
das vilosidades coriais e do trofoblasto extraviloso A despeito de 75-80% das pacientes com NTG tratadas
com MTX alcançarem remissão, 20-25% delas vão cursar com quimiorresistência. Isso ocorre quando há
platô ou aumento nos níveis de hCG, com ou sem desenvolvimento de novas metástases, enquanto a
paciente está sendo tratado com MTX. Este estudo se justifica pois não se conhece o melhor esquema de
tratamento quimioterápico para pacientes com NTG quimiorresistente ao MTX. À exceção da Act-D,
amplamente utilizada no mundo, há apenas um único artigo relatando a experiência no tratamento dessas
mulheres com Carboplatina, assim como é incomum o emprego do Etoposide para esses casos. A falta da
Act-D
Endereço: Rua das Laranjeiras, 180

Bairro: Laranjeiras CEP: 22.240-003
UF: RJ Município: RIO DE JANEIRO
Telefone: (21)2556-9747 Fax: (21)2205-9064 E-mail: cep@me.ufrj.br
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UFRJ - MATERNIDADE
Continuação do Parecer: 2.852.096
no mercado brasileiro, determinou a necessidade do tratamento das pacientes com NTG e

quimiorresistência ao MTX com quimioterápicos pouco usuais. Não existem estudos de coorte nacional que
avaliem esses medicamentos no tratamento de mulheres com NTG. Apresentar os resultados do tratamento
de pacientes com NTG quimiorresistente ao MTX com Carboplatina e do Etoposide nesses casos será
importante para encorpar a literatura com a toxicidade e a efetividade desses medicamentos em pacientes
com NTG.
Objetivo da Pesquisa:
Comparar o desfecho clínico de mulheres com NTG quimiorresistente ao MTX tratadas com Act-D,
Carboplatina ou Etoposide, através dos seguintes objetivos específicos (1)avaliar a remissão de NTG
quimiorresistente ao MTX em mulheres tratadas com Act-D, Carboplatina ou Etoposide; (2) descrever a
toxicidade do tratamento de mulheres com Act-D, Carboplatina ou Etoposide após o diagnóstico de NTG
quimiorresistente ao MTX; (3)estudar o impacto do tratamento de mulheres com Act-D, Carboplatina ou
Etoposide após o diagnóstico de NTG quimiorresistente ao MTX no que tange ao tempo para remissão,
duração do seguimento, sobrevida, recidiva e óbito.
Avaliação dos Riscos e Benefícios:
Segundo os pesquisadores, por ser estudo retrospectivo, não haverá benefícios diretos às pacientes
envolvidas. Todavia, espera-se que esse estudo traga o benefício do maior conhecimento sobre
possibilidades terapêuticas no tratamento de pacientes com NTG quimiorresistente ao MTX, o que se
reveste de grande importância, especialmente no Brasil, onde o abastecimento de Act-D tem sido irregular.
Da mesma forma, não há riscos diretos à saúde das pacientes analisadas. Segundo a resolução 466 de 12
de dezembro de 2012 “ Toda pesquisa com seres humanos envolve risco em tipos e gradações variados”.
Sendo assim, o s pesquisadores assumem que o único risco possível seria indireto, de perder-se a
confidencialidade ou mesmo a integridade dos dados do prontuário. Para maior proteção e confiabilidade, os
prontuários serão examinados dentro de cada instituição, não sendo permitida a reprodução dos
documentos constantes no prontuário, em parte ou no todo. A identidade das pacientes também será
preservada, sendo utilizada na análise do banco de dados apenas a sigla das iniciais dos nomes. Não
obstante, os pesquisadores se comprometem expressamente a manter a confidencialidade dos dados
acessados dos prontuários.
Comentários e Considerações sobre a Pesquisa:

Projeto relevante com desenho de estudo adequado.

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UFRJ - MATERNIDADE
Considerações sobre os Termos de apresentação obrigatória:

Todos apresentados
Recomendações:
Incluir o sr.Rodrigo Bernardes Cardoso, que aparece como pesquisador do projeto na Irmandade Santa
Casa de Misericórdia de Porto Alegre, mas não é citado como membro da pesquisa no relatório de
informações básicas do referido projeto na Plataforma Brasil, caso o mesmo continue no´projeto.
Conclusões ou Pendências e Lista de Inadequações:

Recomenda-se aprovação. Sem pendências.
Considerações Finais a critério do CEP:
Importante lembrar que de acordo com a Resolução CNS 466/2012, no inciso XI.2., assim como a
Resolução CNS 510/2016, cabe ao pesquisador:
d) elaborar e apresentar os relatórios parciais a cada 6 meses e o relatório final ao término do projeto (o site
da
após o término da pesquisa;
g) encaminhar os resultados da pesquisa para publicação, com os devidos créditos aos pesquisadores
associados e ao pessoal técnico integrante do projeto; e
h) justificar fundamentadamente, perante o CEP ou a CONEP, interrupção do projeto ou a não publicação
dos resultados. Plataforma Brasil tem um link para relatório);
e) apresentar dados solicitados pelo CEP ou pela CONEP a qualquer momento;
f) manter os dados da pesquisa em arquivo, físico ou digital, sob sua guarda e responsabilidade, por um
período de 5 anos
OBS.: O parecer consubstanciado, emitido pelo colegiado, encontra-se disponível na árvore lateral esquerda
de arquivos, na pasta “Pareceres”.
Este parecer foi elaborado baseado nos documentos abaixo relacionados:

Tipo Documento Arquivo Postagem Autor Situação
Informações Básicas PB_INFORMAÇÕES_BÁSICAS_DO_P 28/07/2018 Aceito
do Projeto ROJETO_1188218.pdf 16:06:38
Projeto Detalhado / Projeto.doc 28/07/2018 Ana Paula Vieira dos Aceito
Brochura 16:01:53 Santos Esteves
Investigador

Página 03 de 05
UFRJ - MATERNIDADE
Outros termo_de_compromissoUFRJ.pdf 28/07/2018 Ana Paula Vieira dos Aceito

15:56:12 Santos Esteves
Declaração de Parecer.pdf 25/07/2018 Antônio Rodrigues Aceito
Instituição e 18:43:51 Braga Neto
Infraestrutura
Folha de Rosto Folha_de_Rosto.pdf 25/07/2018 Antônio Rodrigues Aceito
18:38:01 Braga Neto
TCLE / Termos de DTCLE.doc 25/07/2018 Antônio Rodrigues Aceito
Assentimento / 12:50:46 Braga Neto
Justificativa de
Ausência
Orçamento Orcamento.doc 24/07/2018 Antônio Rodrigues Aceito
22:03:58 Braga Neto
Declaração de Prontuarios.jpg 24/07/2018 Antônio Rodrigues Aceito
Infraestrutura
Declaração de Onus.jpg 24/07/2018 Antônio Rodrigues Aceito
Infraestrutura
Declaração de Inscricao.jpg 24/07/2018 Antônio Rodrigues Aceito
Infraestrutura
Declaração de Chefia.jpg 24/07/2018 Antônio Rodrigues Aceito
Infraestrutura
Declaração de Cconfidencialidade.jpg 24/07/2018 Antônio Rodrigues Aceito
Infraestrutura
Declaração de UNIFESP.pdf 24/07/2018 Antônio Rodrigues Aceito
Infraestrutura
Cronograma Cronograma.doc 24/07/2018 Antônio Rodrigues Aceito
21:57:38 Braga Neto
Situação do Parecer:
Aprovado
Necessita Apreciação da CONEP:
Não

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UFRJ - MATERNIDADE
RIO DE JANEIRO, 29 de Agosto de 2018
Assinado por:
Ivo Basílio da Costa Júnior
(Coordenador)

Página 05 de 05
UNIFESP - HOSPITAL SÃO
PAULO - HOSPITAL
UNIVERSITÁRIO DA

Elaborado pela Instituição Coparticipante

Methotrexate
Versão: 1
CAAE: 95188418.2.3003.5505
Instituição Proponente: Universidade Federal de São Paulo
DADOS DO PARECER
CEP UNIFESP: POc050/2018 (co-participante)
As informações elencadas nos campos denominados "apresentação do projeto", "objetivo da pesquisa" e

"avaliação dos riscos e benefícios" foram retiradas do documento intitulado
"PB_INFORMAÇÕES_BÁSICAS_1232504_E1.pdf pelo centro coordenador", gerado a partir das
informações inseridas pelo Pesquisador Responsável do estudo na Plataforma Brasil.
O projeto “ Avaliação do tratamento da neoplasia trofoblástica gestacional resistente ao Methotrexate”

tratase de estudo observacional, retrospectivo, colaborativo, de coortes não concorrentes, que avaliará
Carboplatina.
Neoplasia trofoblástica gestacional (NTG) é o termo utilizado para designar lesões malignas que se originam
das vilosidades coriais e do trofoblasto extraviloso A despeito de 75-80% das pacientes
Endereço: Rua Francisco de Castro, 55

Bairro: VILA CLEMENTINO CEP: 04.020-050
UF: SP Município: SAO PAULO
Telefone: (11)5571-1062 Fax: (11)5539-7162 E-mail: cep@unifesp.edu.br
Página 01 de 05
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UNIVERSITÁRIO DA
com NTG tratadas com MTX alcançarem remissão, 20-25% delas vão cursar com quimiorresistência. Isso
ocorre quando há platô ou aumento nos níveis de hCG, com ou sem desenvolvimento de novas metástases,
enquanto a paciente está sendo tratado com MTX. Este estudo se justifica pois não se conhece o melhor
esquema de tratamento quimioterápico para pacientes com NTG quimiorresistente ao MTX. À exceção da
Act-D, amplamente utilizada no mundo, há apenas um único artigo
relatando a experiência no tratamento dessas mulheres com Carboplatina, assim como é incomum o
emprego do Etoposide para esses casos. A falta da Act-D no mercado brasileiro, determinou a necessidade
do tratamento das pacientes com NTG e quimiorresistência ao MTX com quimioterápicos pouco usuais. Não
existem estudos de coorte nacional que avaliem esses medicamentos no tratamento de mulheres com NTG.
Apresentar os resultados do tratamento de pacientes com NTG quimiorresistente ao MTX com Carboplatina
e do Etoposide nesses casos será importante para encorpar a literatura com a toxicidade e a efetividade
desses medicamentos em pacientes com NTG.
Objetivo Primário:
Carboplatina ou Etoposide.
Objetivo Secundário:
Avaliar a remissão de NTG quimiorresistente ao MTX em mulheres tratadas com Act-D, Carboplatina ou
Etoposide.Descrever a toxicidade do tratamento de mulheres com Act-D, Carboplatina ou Etoposide após o
diagnóstico de NTG quimiorresistente ao MTX.Estudar o impacto do tratamento de mulheres com Act-D,
Carboplatina ou Etoposide após o diagnóstico de NTG quimiorresistente ao MTX no que tange ao tempo
para remissão, duração do seguimento, sobrevida, recidiva e óbito

Segundo o pesquisador: Riscos:
Não se prevê riscos diretos à saúde das pacientes analisadas. O único risco possível seria indireto, de
perder-se a confidencialidade ou mesmo a integridade dos dados do prontuário. Para maior proteção e
confiabilidade, os prontuários serão examinados dentro de cada instituição, não sendo

Página 02 de 05
PAULO - HOSPITAL
UNIVERSITÁRIO DA
permitida a reprodução dos documentos constantes no prontuário, em parte ou no todo. A identidade das
pacientes também será preservada, sendo utilizada na análise do banco de dados apenas a sigla das
iniciais dos nomes. Não obstante, os pesquisadores se comprometem expressamente a manter a
confidencialidade dos dados acessados dos prontuários.
Benefícios:
Por ser um estudo retrospectivo, não haverá benefícios diretos às pacientes envolvidas. Todavia, espera-se
que esse estudo traga o benefício do maior conhecimento sobre possibilidades terapêuticas no tratamento
de pacientes com NTG quimiorresistente ao MTX, o que se reveste de grande importância, especialmente
no Brasil, onde o abastecimento de Act-D tem sido irregular
Trata-se de estudo sem obtenção de titulação acadêmica, vinculado ao Departamento de Ginecologia e
Obstetricia da Unifesp, Campus São Paulo, sob a
responsabilidade da Profa Dra Sue Yazaki Sun.
O Centro coordenador será a Maternidade Escola da Universidade Federal do Rio de Janeiro (aprovado
pelo CEP Local), pesquisadores responsável e associado, respectivamente, Antonio Rodrigues Braga Neto
e o Dr. Paulo Alexandre Ribeiro Mora.
Paciente e Métodos. Trata-se de estudo observacional, retrospectivo, colaborativo, de coortes não

concorrentes, que avaliará prontuários médicos de pacientes com diagnóstico de NTG quimiorresistente ao
MTX, acompanhadas no período de 01 de janeiro de 2007 até 31 de dezembro de 2017, tratadas com Act-
D, Etoposide ou Carboplatina. Serão avaliados casos de pacientes com NTG do Centro de Referência em
doença trofoblástica gestacional (CR-DTG) da Maternidade Escola da Universidade Federal do Rio de
Janeiro, do CR da Escola Paulista de Medicina da Universidade Federal de São Paulo e do CR-DTG da
Irmandade da Santa Casa da Misericórdia de Porto Alegre. Serão avaliadas variáveis demográficas,
clínicas, populacionais, critérios de resposta e toxicidade, além de sobrevida, recidiva e óbito. Para analisar
a associação entre os tratamentos quimioterápicos de segunda linha (Act-D, Etoposide ou Carboplatina) e
cada uma das variáveis categóricas, será utilizado o teste exato de Fisher ou qui-quadrado, dependendo
das frequências esperadas sob a hipótese de não associação. Para analisar a semelhança de médias ou de
variáveis numéricas relacionadas aos referidos tratamentos quimioterápicos serão usados os testes de
análise de variância de um fator fixo ou o teste de Kruskal-Wallis, dependendo das distribuições dos dados
numéricos. O nível de significância será definido como um valor de p < 0.05. Será utilizado o Software SPSS
versão 18.0.

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UNIVERSITÁRIO DA

Apresentados os documentos obrigatórios para a Unifesp:
termo de confidencialidade dos dados obtidos ;
justificativa para não obtenção do TCLE;
Recomendações:
Nada consta
sem inadequações para a Unifesp
O CEP informa que a partir desta data de aprovação, é necessário o envio de relatórios parciais
(semestralmente), e o relatório final, quando do término do estudo.

Outros DISPENSADOTERMO.pdf 30/11/2018 Carolina Garcia Aceito
08:50:11
Outros TermodeConf.pdf 30/11/2018 Carolina Garcia Aceito
08:49:07
Outros Emenda.doc 21/11/2018 Antônio Rodrigues Aceito
22:56:20 Braga Neto
Investigador
Justificativa de
Ausência
Aprovado
Não

Página 04 de 05
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UNIVERSITÁRIO DA
SAO PAULO, 21 de Dezembro de 2018
Assinado por:
Miguel Roberto Jorge
(Coordenador(a))

Página 05 de 05
IRMANDADE DA SANTA CASA
DE MISERICORDIA DE PORTO
ALEGRE - ISCMPA

Elaborado pela Instituição Coparticipante

Methotrexate
Versão: 1
CAAE: 95188418.2.3001.5335
Instituição Proponente: Irmandade da Santa Casa de Misericordia de Porto Alegre - ISCMPA
DADOS DO PARECER
O estudo busca comparar o desfecho clínico de pacientes com neoplasia trofoblástica gestacional (NTG)
quimiorresistente ao methotrexate (MTX), submetidas a tratamento com esquemas contendo Actinomicina-D
(Act-D), Etoposide ou Carboplatina.
Trata-se de estudo observacional, retrospectivo, colaborativo, de coortes não concorrentes, que avaliará
Carboplatina. Serão avaliados casos de pacientes com NTG do Centro de Referência em doença
trofoblástica gestacional (CR-DTG) da Maternidade Escola da Universidade Federal do Rio de Janeiro, do
CR da Escola Paulista de Medicina da Universidade Federal de São Paulo e do CR-DTG da Irmandade da
Santa Casa da Misericórdia de Porto Alegre. Serão avaliadas variáveis demográficas, clínicas,
populacionais, critérios de resposta e toxicidade, além de sobrevida, recidiva e óbito. Para analisar a
associação entre os tratamentos quimioterápicos de segunda linha (Act-D, Etoposide ou Carboplatina)
A hipótese é de que a Carboplatina e o Etoposide são opções seguras e efetivas para o tratamento
Endereço: R. Profº Annes Dias,295 Hosp.Dom Vicente Scherer

Bairro: 6º andar - Centro CEP: 90.020-090
UF: RS Município: PORTO ALEGRE
Telefone: (51)3214-8571 Fax: (51)3214-8571 E-mail: cep@santacasa.tche.br
Página 01 de 04
ALEGRE - ISCMPA
de mulheres com NTG quimiorresistente ao MTX, e podem, eventualmente, substituir a Act-D no tratamento
dessa neoplasia.
Objetivo Primário:
Carboplatina ou Etoposide.
Objetivo Secundário:
Avaliar a remissão de NTG quimiorresistente ao MTX em mulheres tratadas com Act-D, Carboplatina ou
Etoposide.Descrever a toxicidade do tratamento de mulheres com Act-D, Carboplatina ou Etoposide após o
diagnóstico de NTG quimiorresistente ao MTX.Estudar o impacto do tratamento de mulheres com Act-D,
Carboplatina ou Etoposide após o diagnóstico de NTG quimiorresistente ao MTX no que tange ao tempo
para remissão, duração do seguimento, sobrevida, recidiva e óbito.

Riscos:
Não se prevê riscos diretos à saúde das pacientes analisadas. O único risco possível seria indireto, de
perder-se a confidencialidade ou mesmo a integridade dos dados do prontuário. Para maior proteção e
confiabilidade, os prontuários serão examinados dentro de cada instituição, não sendo permitida a
reprodução dos documentos constantes no prontuário, em parte ou no todo. A identidade das pacientes
também será preservada, sendo utilizada na análise do banco de dados apenas a sigla das iniciais dos
nomes. Não obstante, os pesquisadores se comprometem expressamente a manter a confidencialidade dos
dados acessados dos prontuários.
Benefícios:
Por ser um estudo retrospectivo, não haverá benefícios diretos às pacientes envolvidas. Todavia, espera-se
que esse estudo traga o benefício do maior conhecimento sobre possibilidades terapêuticas no tratamento
de pacientes com NTG quimiorresistente ao MTX, o que se reveste de grande importância, especialmente
no Brasil, onde o abastecimento de Act-D tem sido irregular.

Estudo retrospectivo que busca analisar a resposta a diferentes tratamento de mulheres com neoplasia
trofoblástica gestacional que foram resistentes ao tratamento com metrotexate. Será analisada uma série de
casos em que os tratamentos foram indicados por motivos assistenciais e observar os desfechos.

Página 02 de 04
ALEGRE - ISCMPA

Justifica-se a não existência de termo de consentimento, sendo substituído por termo de confidencialidade.
Demais documentos estão apresentados corretamente

O presente projeto respeita as normas existentes para realização de pesquisa envolvendo seres humanos.
O projeto tem relevância clínica no sentido de melhorar nosso conhecimento sobre esta doença. Nosso
parecer é favorável a sua aprovação.
Após avaliação do protocolo acima descrito, o presente comitê não encontrou óbices quanto ao
desenvolvimento do estudo em nossa Instituição e poderá ser iniciado a partir da data deste parecer.
Obs.: 1 - O pesquisador responsável deve encaminhar à este CEP, Relatórios de Andamento dos Projetos
desenvolvidos na ISCMPA. Relatórios Parciais (pesquisas com duração superior à 6 meses), Relatórios
Finais (ao término da pesquisa) e os Resultados Obtidos (cópia da publicação).
2 – Para o início do projeto de pesquisa, o investigador deverá apresentar a chefia do serviço (onde será
realizada a pesquisa), o Parecer Consubstanciado de aprovação do protocolo pelo Comitê de Ética.

Informações Básicas PB_INFORMAÇÕES_BÁSICAS_DO_P 17/09/2018 Aceito
do Projeto ROJETO_1210359.pdf 22:04:54
Outros Utilizacao_dados_prontuarios.pdf 17/09/2018 Antônio Rodrigues Aceito
22:04:16 Braga Neto
Outros Inscricao_projeto.pdf 17/09/2018 Antônio Rodrigues Aceito
22:02:15 Braga Neto
Outros Isencao_onus.pdf 17/09/2018 Antônio Rodrigues Aceito
22:01:17 Braga Neto
Outros Autorizacao_chefia.pdf 17/09/2018 Antônio Rodrigues Aceito
22:00:06 Braga Neto

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Outros Confidencialidade_sujeito.pdf 17/09/2018 Antônio Rodrigues Aceito

21:58:57 Braga Neto
Outros Resposta_pendencias_documentais_IS 17/09/2018 Antônio Rodrigues Aceito
CMPA.doc 21:56:26 Braga Neto
Cronograma Cronograma_Projeto_Methotrexate.doc 17/09/2018 Antônio Rodrigues Aceito
21:54:52 Braga Neto
Investigador
Justificativa de
Ausência
Aprovado
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PORTO ALEGRE, 22 de Outubro de 2018
Assinado por:
ELIZETE KEITEL
(Coordenador(a))

Página 04 de 04
World Journal of
WJ C O Clinical Oncology
Submit a Manuscript: https://www.f6publishing.com World J Clin Oncol 2019 February 24; 10(2): 28-37
DOI: 10.5306/wjco.v10.i2.28 ISSN 2218-4333 (online)
EDITORIAL
Challenges in the diagnosis and treatment of gestational

trophoblastic neoplasia worldwide
Antonio Braga, Paulo Mora, Andréia Cristina de Melo, Angélica Nogueira-Rodrigues, Joffre Amim-Junior,
Jorge Rezende-Filho, Michael J Seckl
ORCID number: Antonio Braga Antonio Braga, Paulo Mora, Postgraduate Program of Medical Sciences, Fluminense Federal
(0000-0002-2942-6182); Paulo Mora University, Niterói 24033-900, Brazil
(0000-0003-1756-3320); Andréia
Cristina de Melo Antonio Braga, Joffre Amim-Junior, Jorge Rezende-Filho, Department of Gynecology and
(0000-0002-1201-4333); Angélica Obstetrics, Faculty of Medicine, Rio de Janeiro Federal University, Postgraduate Program of
Nogueira-Rodrigues Perinatal Health, Maternity School, Rio de Janeiro 22240-000, Brazil
(0000-0002-3405-8310); Joffre Amim-
Junior (0000-0002-9890-6972); Jorge Paulo Mora, Andréia Cristina de Melo, Brazilian National Cancer, Hospital do Câncer 2, Rio de
Rezende-Filho Janeiro 20220-410, Brazil
(0000-0002-2193-3374); Michael J
Seckl (0000-0003-4078-2599). Angélica Nogueira-Rodrigues, Department of Internal Medicine, Faculty of Medicine, Minas
Gerais Federal University, Belo Horizonte 30130-100, Brazil
Author contributions: Braga A and
Seckl MJ conceived the study; all Michael J Seckl, Department of Medical Oncology, Charing Cross Gestational Trophoblastic
authors drafted the manuscript Disease Centre, Charing Cross Hospital, Imperial College London, London W6 8RF, United
and approved the final version of
the article.
Kingdom
Conflict-of-interest statement: The Corresponding author: Antonio Braga, MD, PhD, Professor, Department of Gynecology and
authors have no conflict of interest Obstetrics, Faculty of Medicine, Rio de Janeiro Federal University, Postgraduate Program of
to declare. Perinatal Health, Maternity School, Rua das Laranjeiras, 180, Laranjeiras, Rio de Janeiro
22240-000, Brazil. bragamed@yahoo.com.br
Open-Access: This article is an Telephone: +55-21-992040007
open-access article which was Fax: +55-21-22857935
selected by an in-house editor and
fully peer-reviewed by external
reviewers. It is distributed in
accordance with the Creative
Commons Attribution Non
Abstract
Commercial (CC BY-NC 4.0) Gestational trophoblastic neoplasia (GTN) is a rare tumor that originates from
license, which permits others to pregnancy that includes invasive mole, choriocarcinoma (CCA), placental site
distribute, remix, adapt, build trophoblastic tumor and epithelioid trophoblastic tumor (PSTT/ETT). GTN
upon this work non-commercially,
and license their derivative works
presents different degrees of proliferation, invasion and dissemination, but, if
on different terms, provided the treated in reference centers, has high cure rates, even in multi-metastatic cases.
original work is properly cited and The diagnosis of GTN following a hydatidiform molar pregnancy is made
the use is non-commercial. See: according to the International Federation of Gynecology and Obstetrics (FIGO)
http://creativecommons.org/licen 2000 criteria: four or more plateaued human chorionic gonadotropin (hCG)
ses/by-nc/4.0/
concentrations over three weeks; rise in hCG for three consecutive weekly
Manuscript source: Invited measurements over at least a period of 2 weeks or more; and an elevated but
manuscript falling hCG concentrations six or more months after molar evacuation. However,
the latter reason for treatment is no longer used by many centers. In addition,
Received: August 1, 2018 GTN is diagnosed with a pathological diagnosis of CCA or PSTT/ETT. For
Peer-review started: August 1, 2018 staging after a molar pregnancy, FIGO recommends pelvic-transvaginal Doppler
First decision: August 31, 2018 ultrasound and chest X-ray. In cases of pulmonary metastases with more than 1
WJCO https://www.wjgnet.com 28 February 24, 2019 Volume 10 Issue 2

Braga A et al. Gestational trophoblastic neoplasia
Revised: November 12, 2018 cm, the screening should be complemented with chest computed tomography
Accepted: January 1, 2019 and brain magnetic resonance image. Single agent chemotherapy, usually
Article in press: January 1, 2019 Methotrexate (MTX) or Actinomycin-D (Act-D), can cure about 70% of patients
Published online: February 24, with FIGO/World Health Organization (WHO) prognosis risk score ≤ 6 (low
2019
risk), reserving multiple agent chemotherapy, such as EMA/CO (Etoposide,
MTX, Act-D, Cyclophosphamide and Oncovin) for cases with FIGO/WHO
prognosis risk score ≥ 7 (high risk) that is often metastatic. Best overall cure rates
for low and high risk disease is close to 100% and > 95%, respectively. The
management of PSTT/ETT differs and cure rates tend to be a bit lower. The early
diagnosis of this disease and the appropriate treatment avoid maternal death,
allow the healing and maintenance of the reproductive potential of these women.
Key words: Gestational trophoblastic neoplasia; Chemotherapy; Chorionic gonadotropin;

Invasive mole; Choriocarcinoma; Placental site trophoblastic tumor; Epithelioid
trophoblastic tumor
©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: Gestational trophoblastic neoplasia is a cancer that originates from placental
tissue, with potential for invasion and widespread metastasis. It secretes human chorionic
gonadotrophin, which serves as a highly useful biomarker that contributes to the
diagnosis, monitoring of therapeutic response, subsequent early detection of relapse and
assessment of cure. Once the diagnosis is made, staging and International Federation of
Gynecology and Obstetrics/World Health Organization prognostic risk score should be
obtained, to initiate the treatment of choice – chemotherapy, which allows high cure
rates, especially if the treatment occurs in Reference Centers, which has specialized staff
in the treatment of this neoplasm.
Citation: Braga A, Mora P, de Melo AC, Nogueira-Rodrigues A, Amim-Junior J, Rezende-

Filho J, Seckl MJ. Challenges in the diagnosis and treatment of gestational trophoblastic
neoplasia worldwide. World J Clin Oncol 2019; 10(2): 28-37
URL: https://www.wjgnet.com/2218-4333/full/v10/i2/28.htm
DOI: https://dx.doi.org/10.5306/wjco.v10.i2.28
INTRODUCTION
Gestational trophoblastic neoplasia (GTN) is a rare tumor that originates from
pregnancy and, if treated in reference centers, has high cure rates, even in cases of
multi-metastatic neoplasia[1,2]. GTN includes the following histopathological forms:
Invasive mole (IM), choriocarcinoma (CCA), placental site trophoblastic tumor (PSTT)
and epithelioid trophoblastic tumor (ETT), encompassing lesions that originate in the
chorionic villi and the extravillous trophoblast, with different degrees of proliferation,
invasion and dissemination[3]. About 50% of all cases of GTN occur after hydatidiform
mole, 25% after abortions or ectopic pregnancies and 25%, after term or preterm
deliveries. However, PSTT and ETT can arise after term deliveries or non-molar
pregnancies in 95% of the cases[4].
Although GTN is a highly metastatic and lethal neoplasia, its natural history was
modified in the 1950s, when Li et al[5] introduced Methotrexate (MTX) as an effective
antineoplastic treatment to promote the systematic cure of women with non-
metastatic disease. Further advances, combined multiple drugs, notably those with
etoposide and cisplatin, allowed high remission rates, even in cases of disseminated
neoplasia[6,7].
With the establishment of chemotherapy in the treatment of GTN, the
systematization of the diagnosis and GTN staging proposed by the International
Federation of Gynecology and Obstetrics (FIGO), held at the Washington meeting in
2000, represented a great advance in the treatment of women with GTN[8]. The FIGO
2000 guideline not only standardized the GTN classification, but also proposed well-
established diagnostic and therapeutic criteria and standardized the risk factors for
chemoresistance, highlighting patients who would benefit from initial treatment with
a single agent or, on the contrary, signaling patients who should be initially treated

with multiple agent chemotherapy[8]. However, it is important to note that the FIGO
2000 criteria should not be applied to the management of PSTT/ETT which be-have
quite differently from the other forms of GTN.
After more than 15 years of the FIGO 2000 guideline implementation for the
diagnosis and treatment of GTN, many questions arose as real challenges for the
treatment of women with GTN[9]. The purpose of this editorial will be to discuss the
situations that still limit the best treatment of GTN, as well as to reflect on alternatives
to improve the treatment of women with this condition worldwide.
BASIC OF GTD PATHOLOGY

The commonest forms of GTD are complete and partial molar pregnancies. Their
cytogenetic origin derives from an abnormal fertilization. In cases of complete
hydatidiform mole, the oocyte loses its DNA, being fertilized by 1 spermatozoa with
diploid genetic load, or by 2 haploid spermatozoa - generating a diploid
parthenogenetic zygote. In the cases of partial hydatidiform mole, the oocyte has
conserved its DNA, being fertilized by 1 spermatozoa with diploid genetic load, or by
2 haploid spermatozoa - generating an zygote with a diandrical triploidy. Women
with complete hydatidiform mole may develop postmolar GTN about 20%-25%,
while only 1%-5% of women with partial hydatidiform mole will present malignant
lesions.
The presence of chorionic villi in the myometrium, with or without vascular
invasion, characterizes the IM, the most common form of GTN. Usually its diagnosis
is obtained through the uterine histopathology obtained by hysterectomy.
CCA is the most malignant and metastatic form of GTN. Although it’s primary
lesion usually presents with great uterine invasion, in about 30% of the cases it crosses
with distant metastases, notably in the lungs, liver and brain, by hematogenous
dissemination.
Among the non-villous lesions that make up a GTN, PSTT and ETT are derived
from the intermediate trophoblast. These clinical forms exhibit lower levels of hCG
relative to invasive spring and CCA. In addition, the therapeutic response of PSTT
and ETT to chemotherapy alone is limited, requiring hysterectomy to maximize cure
rates.
HOT TOPICS ON GTN DIAGNOSIS AND STAGING

The FIGO 2000 guideline established the diagnostic criteria for GTN that would
determine the immediate onset of chemotherapy[8]: (1) Four or more plateaued hCG
concentrations over three weeks; (2) Increase of hCG concentrations for three or more
consecutive measurements for at least two weeks; (3) If there is a histologic diagnosis
of choriocarcinoma; and (4) Elevated hCG concentrations for six months or longer.
It should be highlighted that the fundamental pillar of the GTN diagnosis is the
hormonal surveillance of serum hCG, the biological and tumor marker of this disease.
However, two situations pointed out by FIGO 2000 guideline are currently being
questioned. The first relates to whether chemotherapy needs to always be initiated for
women with a histopathological diagnosis of CCA. The second concerns if
chemotherapy is really needed for patients whose hCG remains raised but falling
beyond the 6 mo after uterine evacuation of a molar pregnancy.
Prior literature unanimously suggests immediate onset of chemotherapy for
patients with metastatic CCA or with elevated rising hCG. However, there are not
infrequent cases of patients who arrive at referral centers with histological diagnosis
of CCA and who have declining or even normal levels of hCG, without evidence of
metastatic disease. This situation can happen because the histopathological diagnosis
of CCA is not always given quickly and/or because the disease was completely
resected at the time of diagnosis. A Brazilian retrospective cohort study that followed
47 women with a histopathological diagnosis of CCA managed expectantly, observed
that only 44.7% received chemotherapy due to plateauing or rising hCG level after an
initial follow up of 2-3 wk[10]. It is noteworthy that the expectant management initially
adopted for patients with histological diagnosis of CCA when compared to patients
immediately treated with chemotherapy did not worsen the prognosis of these
patients, besides no cases of relapse or death were found in this population studied[10].
Regarding the FIGO 2000 recommendation to initiate chemotherapy for patients
during postmolar follow-up with hCG raised but falling after 6 mo of uterine
evacuation, FIGO itself is controversial, once retracted this opinion in 2012[11], but then
resumed the recommendation in the FIGO Cancer Report in 2015[12]. Although this

situation is uncommon, affecting about 1% of the women in the post-molar follow-up,

expectant management has about 80% spontaneous remission, without the need for
chemotherapy[13-15]. These results are more favorable, the lower the hCG levels. No
woman developed relapsed disease and overall survival was 100%[13-15]. It is likely that
the new FIGO Cancer Report due out in 2018 will recommend that automatic
chemotherapy should not be started in this group of women and that continued hCG
surveillance is reasonable.
Delaying the onset of chemotherapy, as recommended by the FIGO criteria, could
lead to the occurrence of tumor chemoresistance or even metastatic disease and the
need for multiple agent chemotherapy [15] . However, the data available shows
continued surveillance avoids exposing women unnecessarily to potential toxicities of
chemotherapy without increase the risk of resistance or more aggressive treatment
later, if necessary[13-15]. In settings where patients with nonmetastatic CCA or with a
raised but falling hCG beyond 6 mo from uterine can only be followed with periodic
measurements of hCG and evaluation of metastatic disease, since the vast majority of
these women will present spontaneous remission[15].
Despite the nearly universal acceptance of the FIGO 2000 criteria to initiate
chemotherapy for patients with GTN[8], there is still a set of recommendations initially
outlined by the Charing Cross Trophoblastic Disease Center (London, United
Kingdom), which were adopted by the European Organization for the Treatment of
Trophoblastic Disease (EOTTD)[3,16]. Although plateau or elevated hCG remains the
most important diagnostic criteria for GTN, many countries worldwide consider
immediate indication for chemotherapy serum hCG concentration of ≥ 20000 IU/L
four weeks or more after uterine evacuation, due to the increased chance of such
patients developing GTN and/or uterine perforation. Despite the United Kingdom
recommendations[3,16], this indication for chemotherapy has not been adopted by
FIGO[8].
A Brazilian study confirmed the increased risk for developing postmolar GTN in
patients with an hCG ≥ 20000 IU/L four weeks after evacuation, about 80% [17] .
However, this study did not report any uterine perforation or to an increase in the
aggressiveness of chemotherapy when comparing the groups of women immediately
treated with those in which an initial expectant treatment was adopted. In fact,
maintaining hormonal surveillance among women with hCG levels higher than 20000
IU/L in the fourth week after molar evacuation would prevent unnecessary
chemotherapy in 20% of women[17]. However, the study population was small and
further validation work in a larger population would be desirable.
Once the clinical diagnosis of GTN has been made following a histopathological
diagnosis of a molar pregnancy, repeat biopsies to confirm malignant progression are
unnecessary and nearly always contraindicated because of the risk of promoting life-
threatening hemorrhage. Indeed, as samples are usually taken from the uterus in
women of reproductive age who can expect to be cured by chemotherapy, a biopsy
might result in a hysterectomy or loss of life which is reprehensible[18]. Moreover,
biopsies of metastatic sites where bleeding cannot be controlled such as the lungs and
abdominal/pelvic organs may precipitate severe hemorrhage, resulting in death[18]. In
addition, it should be always considered that the diagnosis of GTN, in almost all
cases, is hormonal - by the evaluation of the hCG behavior[19].
Before initiating chemotherapy, staging of GTN is critical. And here are two
differences that must be stressed. While in the United States, initial staging with brain
and abdomen-pelvis magnetic resonance imaging (MRI), and chest computed
tomography (CT) is recommended[20], FIGO/EOTTD recommends that only pelvic-
transvaginal Doppler ultrasound and chest X-ray should be initially requested in
patients with post-molar GTN. In cases of doubts regarding the normality of the chest
X-ray or in the case of metastases with more than 1cm, the screening of metastases
with chest CT and brain MRI should be complemented[3,8]. The major problem of using
CT rather than chest X-ray for assessing the presence of pulmonary metastases
following a molar pregnancy is the risk of including micrometastases < 1 cm. This will
upstage and or increase the prognostic score for patients leading to more women
starting on multi-agent chemotherapy than necessary. Indeed, several studies have
shown that CT defined chest micro-metastasis as opposed to chest X-ray defined
pulmonary metastases does not affect outcomes and should not influence
staging/scoring or the selection of chemotherapy[21,22].
The role of positron emission tomography (PET), associated or not to CT in the
evaluation of metastatic GTN, has not yet been well established[22]. The available
information points out that the PET does not add anything to the GTN staging when
compared to conventional imaging work-up that is less expensive and more widely
available. PET may help to evaluate metastases in unusual sites or to differentiate
active metastatic nodules from necrotic and/or hemorrhagic tissue following
chemotherapy and in cases of chemoresistance or relapse, notably in patients with

PSTT or ETT, for guiding surgical intervention[22,23]. Both false positive and negative
results can occur with FDG-PET imaging so careful co-evaluation with other imaging
modalities is desirable[24].
PERSPECTIVES OF THE TREATMENT ON GTN

Before discussing GTN treatment in detail, we will initially consider the use of
prophylactic chemotherapy for cases of hydatidiform mole thought to be at high risk
of developing GTN. The criteria for diagnosing such high risk moles varies and
includes very high hCG at the time of evacuation and women who are unable to
comply with an hCG surveillance programme following the molar evacuation.
Although there is a clear reduction in the risk of development of postmolar GTN[25],
the use of prophylactic chemotherapy may increase patients' morbidity (by the side
effects of cytotoxic drugs), the risk of chemoresistance, and medical care costs, for the
treatment of a neoplasm fully curable without the use of prophylactic
chemotherapy[26]. While there is no clear scientific evidence about the benefits of using
prophylactic chemotherapy for cases of high-risk hydatidiform mole, we agree that it
is time to stop recommending prophylactic chemotherapy for these women[27].
Similarly, prophylactic hysterectomy for the treatment of high-risk hydatidiform
mole, or even as primary GTN treatment, should only be considered in women that
completed childbearing[28]. However, what we have observed in several settings across
the world is that women frequently underwent hysterectomy as their main treatment
for a suspected molar pregnancy. Apart from preventing such women from getting
pregnant in the future, many fail to then adhere to hCG surveillance because they
think they are cured after surgery[18]. This is a serious problem as a significant number
will still end up needing chemotherapy due to growth of micrometastases outside the
uterus. These patients will be diagnosed late if they are not on hCG surveillance and
so worsen their prognosis.
It has also been pointed out that second curettage for some patients diagnosed with
GTN can avoid the need for starting chemotherapy. Although the outcomes are
controversial and the studies are either small, non-randomised[29] or retrospective in
design[30,31], a reduction in the need for chemotherapy was observed between 9%-40%
of the patients undergoing a second curettage. Nevertheless, whilst the efficacy of this
procedure remains unclear, the benefit appears to be greatest only in patients with
non-metastatic GTN and levels of hCG below 5000 IU/L[29-31].
The choice of chemotherapy treatment is based on the combination of the anatomic
staging with the World Health Organization (WHO) scoring system based on risk
factors[8] (Table 1). According to this scoring system, tumors are divided into two
categories: Low-risk GTN, if the score is equal to or lower than 6; and high-risk, if the
score is equal to or greater than 7. The score is associated with the risk of developing
chemoresistance, and thus guides the choice of first line chemotherapy[8].
Low-risk GTN should be first treated with a single agent, either MTX or
Actinomycin-D (ActD)[32,33]. Although a Cochrane review points to a superiority of
Act-D over MTX [34] , what we observe is that there are numerous chemotherapy
regimens for either MTX (50 mg fixed dose or 50 mg/m2 or 1 mg/kg on days 1, 3, 5, 7,
with or without folinic acid rescue, 0.4 mg/kg D1-5, 30-50 mg/m2 once weekly), and
for Act-D (10-13 mcg/kg D1-5, 1.25 mg/m2 biweekly), making it impossible, with the
data available, to actually evaluate the best initial treatment for low-risk GTN[32-34].
Although cases of low-risk GTN are widely cured with single agent
chemotherapy[8,32,33], it has been observed that patients with GTN and with a FIGO
score of 5-6 only have about a 35% chance of cure with MTX regimen. This indicates
that these patients form an “intermediate-risk group”, for whom the MTX regimen
might be considered to be relatively unlikely to achieve a cure[35]. For these patients,
one could either start on a more aggressive chemotherapy regimen, or develop a new
assessment which could be added to the existing scoring system to enable improved
patient stratification to single verses multi-agent therapy. Recent work suggests that
the uterine artery pulsatility index[36], might help to identify patients resistant to MTX
treatment. However, it is still unclear how to incorporate the pulsatility index into the
FIGO scoring system.
Indeed, there is an international scientific effort to validate the FIGO/WHO
prognostic risk score[37]. Studies have shown that of the eight patients who had a pre-
treatment hCG exceeding 10000 IU/L and 100000 IU/L, interval exceeding 7 mo since
previous pregnancy and tumor size of over 5 cm were identified as being predictive of
single-agent resistance [38] . Another perspective shows that no patient with pre-
treatment hCG level higher than 400000 IU/L achieve remission under single agent
chemotherapy treatment, regardless of the prognostic risk score[39].

Table 1 International Federation of Gynecology and Obstetrics/World Health Organization staging and classification of gestational
trophoblastic disease
GTN: FIGO staging and classification (Washington, 2000)
FIGO anatomic staging

Stage I: Disease confined to the uterus
Stage II: GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament)
Stage III: GTN extends to the lungs, with or without known genital tract involvement
Stage IV: All other metastatic sites
Modified WHO prognostic scoring system as adapted by FIGO
Prognostic factors Score
0 1 2 4
Age < 40 ≥ 40 - -
Antecedent gestation Mole Abortion Term -
Interval (mo) <4 4-6 7-12 > 12
Pretreatment serum hCG (IU/L) < 103 103 to < 104 104 to < 105 > 105
Largest tumor size (including uterus) <3 3 to 4 ≥5 -
Site of metastases Lung spleen, kidney gastro intestinal tract brain, liver
Number of metastases - 1-4 5-8 >8
Previous failed chemotherapy - - single drug 2 or more drugs
Interval (in months) between the end of antecedent gestation (when known) and symptom onset. FIGO: International Federation of Gynecology and
Obstetrics; WHO: World Health Organization; GTN: Gestational trophoblastic neoplasia; hCG: Human chorionic gonadotropin.
Less commonly, patients reach referral centers for treatment with high-risk GTN
and disseminated disease. These patients were usually treated with the regimen of
choice for high-risk GTN [3,8,32] : EMA/CO (combining Etoposide, MTX, Act-D,
Cyclophosphamide and Oncovin). Initial reports indicated a survival rate of about
86% with deaths occurring either early within 4 wk of admission due mainly to
bleeding or metabolic upset from tumor lysis in patients with very advanced disease
or late from drug resistant disease. In addition, some deaths were due to non-
gestational tumors that histopathologically mimicked GTN[40]. To avoid these early
deaths, high risk GTN patients with a FIGO score ≥ 13, with or without a higher
number of metastases (> 6) and higher hCG (> 1000000 IU/L), seem to benefit from
the use of induction low-dose Etoposide 100 mg/m2 and cisplatin 20 mg/m2 (EP; days
1 and 2 every 7 d) for one to three cycles until well enough to start EMA/CO[40].
Although more than 90% of patients with GTN are cured with chemotherapy
regimens based on Etoposide and Cisplatin [3,8,32] , there are some patients with
chemoresistant neoplasia who present a major therapeutic challenge. In such cases,
one must try to obtain tumor tissue to determine the genetic origin of CCA
(gestational verses non-gestational) and to rule out the possibility of PSTT/ETT
(where treatment necessarily includes surgery) [3,8,32] . Indeed, the management of
PSTT/ETT is quite different reflecting its distinct biological behavior. The disease is
slower growing, produces less hCG, remains confined to the uterus for longer, is more
likely to involve local lymph nodes and is a little more resistant to chemotherapy than
CCA[41]. It is now appreciated that all types of preceding pregnancy can give rise to
PSTT/ETT and that the key poor prognostic factor is an interval more than 4 years
from the last known or causative pregnancy[42]. Moreover, recent work has revealed
that 10%-15% of women with atypical placental site nodules (APSN) may either have
a co-existent or subsequently develop a PSTT/ETT so APSN can no longer be
ignored[43]. Patients with histologically confirmed PSTT/ETT confined to the uterus
are best managed with hysterectomy whilst those with metastatic disease will need
combination agent chemotherapy followed by resection of residual disease sites.
Patients with an interval more than 4 years from the causative pregnancy are unlikely
to be cured with regular platinum and etoposide based chemotherapy regimens such
as EP/EMA plus surgery and so should be considered for experimental systemic
therapies regardless of stage[42]. Some GTN patients including those with PSTT/ETT
who have disease with some sensitivity to platinum and etoposide may still be
salvaged with high dose chemotherapy but other more effective and less toxic
alternatives are needed[3]. In studying the immuno-expression of these tissues, it has
been found that PD-L1 and its receptor PD-1 are strongly expressed by GTN,
suggesting the ligand is involved in tumor-immune evasion[44]. Indeed, a few cases of

multi drug-resistant GTN including PSTT/ETT have recently shown complete

responses to the anti-PD-1 agent Pembrolizumab with several women off treatment
and well for 6-24 mo[45]. Therefore, it is tempting to speculate that such checkpoint
immunotherapies may provide a new effective salvage treatment for women with
GTN failing existing therapies and that this might replace the need for high dose
chemotherapy.
Despite the great improvement observed in the treatment of women with GTN,
especially in the methods of disease monitoring, more accurate metastasis screening
and more effective treatments, even in multimetastatic cases, we believe that the most
important key for survival of women affected by this disease is their treatment in
Reference Centers. Brewer was the first to report that both the morbidity and
mortality of patients with GTN was nine times lower at a center staffed by physicians
experienced in the management of this neoplasia than with the “occasional” physician
treating this entity [46] . Moreover, the UK experience of centralized care within a
national health system has provided an exemplar of what can be achieved with the
UK specialized centers reporting the highest cure rates globally[47]. The Brazilian
experience now also clearly shows that when these patients are followed in Reference
Centers they demonstrate lower metastasis rate, lower median time interval between
molar evacuation and chemotherapy onset shorter than those initially treated outside
the Reference Centers[48].
Between advances[49-51] and challenges[52], the truth is that GTN is still an unknown
disease of many physicians in the world. When the obstetrician is unable to recognize
this anomaly of pregnancy, postponing its diagnosis[53,54]; when the gynecologist does
not understand the importance of hormonal vigilance and strict contraception during
this period[55,56]; when the oncologist indicates unnecessary surgeries to treat women
with GTN or uses incorrect chemotherapy regimens, our women with GTN will
suffer, sometimes losing their uterus or even their lives. Figure 1 briefly illustrates the
entire treatment of GTD.
It is important to highlight that GTN can arise from any pregnancy form (abortion,
ectopic, term/preterm, and, of course after hydatidiform mole), and that it should be
ruled out in cases of metastatic neoplasia in women during the menacme, with
unknown primary site, especially if the clinical history reveals a recent gestational
history. Finally, it is important to remember, that a simple hCG test may help provide
the diagnosis of this neoplasia, monitor the treatment, confirm the cure and detect
relapse early to enable effective salvage therapy.

Figure 1
Figure 1 Algorithm summarizing the modern treatment of gestational trophoblastic neoplasia. GTN: Gestational trophoblastic neoplasia; hCG: Human
chorionic gonadotropin.
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P- Reviewer: Kanat O, Kupeli S, Ortiz-Sanchez E

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Gynecologic Oncology 153 (2019) 277–285
Contents lists available at ScienceDirect
Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno
Can carboplatin or etoposide replace actinomycin-D for second-line

treatment of methotrexate resistant low-risk gestational
trophoblastic neoplasia?
Paulo Alexandre Ribeiro Mora a,b,c, Sue Yazaki Sun d, Guillermo Coca Velarde b, Jorge Rezende Filho a,e,
Elza H. Uberti f, Ana Paula Vieira dos Santos Esteves a,e, Kevin M. Elias g, Neil S. Horowitz g,
Antonio Braga a,b,e,⁎, Ross S. Berkowitz g
a
Rio de Janeiro Trophoblastic Disease Center, Maternity School of Rio de Janeiro Federal University, Antonio Pedro University Hospital, Fluminense Federal University, Rio de Janeiro, RJ, Brazil
b
Postgraduate Program in Medical Sciences, Fluminense Federal University, Niterói, RJ, Brazil
c
Brazilian National Cancer, Hospital do Câncer 2, Rio de Janeiro, RJ, Brazil
d
São Paulo Hospital Trophoblastic Disease Center, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
e
Postgraduate Program in Perinatal Health, Faculty of Medicine, Maternity School of Rio de Janeiro Federal University, Rio de Janeiro, RJ, Brazil
f
Porto Alegre Trophoblastic Disease Center, Mario Totta Maternity Ward, Irmandade da Santa Casa de Misericórdia Hospital, Porto Alegre, RS, Brazil
g
New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical
School, Boston, MA, USA
H I G H L I G H T S
• Actinomycin-D and etoposide achieved higher remission rates than carboplatin as a second-line regimen for low-risk GTN.
• Carboplatin caused more hematologic toxicity and treatment delays than actinomycin-D or etoposide.
• Carboplatin required greater utilization of G-CSF for neutropenia than actinomycin-D.
a r t i c l e i n f o a b s t r a c t
Article history: Objective. To evaluate the impact of periodic shortage of actinomycin-D (Act-D) in the treatment of Brazilian
Received 4 January 2019 patients with low-risk gestational trophoblastic neoplasia (GTN) after methotrexate and folinic acid rescue
Received in revised form 1 March 2019 (MTX/FA) resistance, treated alternately with carboplatin or etoposide as a second-line regimen.
Accepted 4 March 2019
Methods. Retrospective cohort that included patients with failure of first-line MTX/FA regimen for low-risk
Available online 8 March 2019
GTN treated at Rio de Janeiro Federal University, Universidade Federal de São Paulo and Irmandade da Santa
Keywords:
Casa de Misericórdia de Porto Alegre, from January/2010- December/2017.
Gestational trophoblastic neoplasia Results. From 356 patients with low-risk GTN treated with MTX/FA, 75 (21.1%) developed resistance, of which
Methotrexate-resistance 40 (53.3%) received Act-D, 23 (30.7%) carboplatin and 7 (9.3%) etoposide. Although patients treated with single-
Actinomycin-D agent chemotherapy as a second-line regimen had comparable clinical and primary treatment characteristics,
Carboplatin those treated with Act-D (80%, p = 0.033) or etoposide (71.4%, p = 0.025) had higher remission rates when com-
Etoposide pared with carboplatin (47.8%). Only 29% of patients treated with carboplatin received the chemotherapy cycles
without delay compared to Act-D (98%, p b 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 b 0.001) and thrombocytopenia (43.4%, p b 0.001), as well as a higher occurrence of febrile neutropenia
(14.4%, p = 0.044) and vomiting (60%, p b 0.001) than those receiving Act-D (5%, none, 2.5%, none, 10%, respec-
tively).
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.
© 2019 Elsevier Inc. All rights reserved.
⁎ Corresponding author at: Gestational Trophoblastic Disease Center of Rio de Janeiro, Maternidade Escola, Universidade Federal do Rio de Janeiro, Rua Laranjeiras, 180, Laranjeiras, Rio
de Janeiro, RJ CEP: 22240-003, Brazil.
E-mail address: antonio.braga@ufrj.br (A. Braga).
0090-8258/© 2019 Elsevier Inc. All rights reserved.
278 P.A.R. Mora et al. / Gynecologic Oncology 153 (2019) 277–285
1. Introduction This study describes the results of treatment of Brazilian patients

with MTX/FA-resistant low-risk GTN with actinomycin-D, carboplatin
Gestational trophoblastic neoplasia (GTN) includes a group of tu- or etoposide, and compares our experience with the literature. Impor-
mors derived from the human trophoblast, comprising invasive mole, tantly, in an era when global markets have frequent shortages of
choriocarcinoma (CCA), placental site trophoblastic tumor (PSTT) and chemotherapies, it is critical to evaluate the efficacy of alternative
epithelioid trophoblastic tumor (ETT). Generally, GTN is highly respon- treatments [20,21].
sive to chemotherapy and has a sensitive tumor marker, human
chorionic gonadotrophin (hCG), that allows monitoring response to 2. Material and methods
treatment and assuring disease remission [1].
Because GTN is uncommon, patients with this disease may benefit 2.1. Study design
from treatment in Reference Centers, where survival rates approach
100%, especially when the GTN is diagnosed early [2]. Choice of chemo- This is a collaborative retrospective cohort study of patients with
therapy for GTN is based on the International Federation of Gynecology GTN followed at Maternity School of Rio de Janeiro Federal University
and Obstetrics (FIGO) staging and World Health Organization (WHO) (Rio de Janeiro – RJ, Brazil, data entered by PARM and audited by AB),
risk score system that evaluates prognostic factors for resistance to São Paulo Hospital Trophoblastic Disease Center of Universidade Federal
single-agent therapy [1]. Patients with stage I, II or III disease and a de São Paulo (São Paulo – SP, Brazil, data entered by PARM and audited
FIGO/WHO risk score ≤ 6, are considered to have low-risk GTN and are by SYS) and Mario Totta Maternity Ward at Irmandade da Santa Casa de
treated with single-agent chemotherapy, usually methotrexate and Misericórdia Hospital (Porto Alegre – RS, Brazil, data entered by PARM
folinic acid rescue (MTX/FA) or actinomycin-D (Act-D), with primary re- and audited by EHU), from January 2010 to December 2017.
mission rates ranging from 70 to 90% [1]. The risk for resistance to a This study was approved by the local Institutional Review Board
single-agent regimen is increased among patients with low-risk GTN associated with the Brazilian Research Ethics Committee of the
with FIGO/WHO risk scores of 5–6 and clinicopathologic diagnosis of Maternity School of the Rio de Janeiro Federal University (CAAE
choriocarcinoma. Even in these cases, salvage chemotherapy can cure 95188418.2.0000.5275), São Paulo Hospital of Universidade Federal de
N90% of these patients [1]. São Paulo (CAAE 95188418.2.3003.5505) and Mario Totta Maternity
In Brazil, the Brazilian Association of Gestational Trophoblastic Dis- Ward at Irmandade da Santa Casa de Misericórdia de Porto Alegre
ease (BAGTD) has established treatment protocols for patients with (CAAE 95188418.2.3001.5335).
low-risk GTN [3]. While there is no clear global consensus on the pre-
ferred single-agent treatment [4], BAGTD recommends MTX/FA as a 2.2. Study participants
first-line chemotherapy for these patients [3]. In cases of MTX/FA
chemoresistance, Act-D is proposed as a second-line regimen, reserving Patients diagnosed with low-risk GTN according to the FIGO 2000
the etoposide, methotrexate, actinomycin-D, cyclophosphamide, criteria [22], that had a diagnosis of MTX/FA-resistance and were subse-
oncovin (vincristine) (EMA/CO) regimen as salvage chemotherapy [3]. quently treated with Act-D, carboplatin or etoposide were included in
However, since 2013, Brazil has experienced periodic shortages of this study. All patients were followed up for at least 12 months after re-
Act-D, compromising the treatment of GTN in patients with MTX/FA remission. All cases of molar pregnancy that developed GTN or choriocar-
sistance. In this period, despite institutional efforts made by the BAGTD, cinoma had their diagnosis confirmed by the Pathology Department of
Brazilian Federation of Gynecology and Obstetrics Associations and the the Reference Centers. Patients diagnosed with high-risk GTN, PSTT
Brazilian Society of Clinical Oncology, to facilitate market availability of and ETT, and patients treated with multiagent regimens as their
Act-D, Brazilian physicians treating GTN have necessarily sought thera- second-line therapy following the diagnosis of MTX/FA-resistance
peutic alternatives. Without access to Act-D, two alternative single- were excluded. Patients with MTX/FA treatment failure due to toxicity
agents were used to treat women with MTX/FA chemoresistance: were also excluded from this study, to make the results more compara-
carboplatin or etoposide. ble to those of Winter et al. [11], that only included patients who devel-
Carboplatin is an alkylating organoplatinum compound that as part oped MTX/FA resistance.
of multiagent regimens has been shown to be safe and effective in the
treatment of women with GTN [5–10]. Winter et al. [11], showed for 2.3. Sample size
the first time that carboplatin as a single-agent induced remission in
81% of women with MTX/FA chemoresistant low-risk GTN. The authors In the recent report by Winter, et al. [11], the complete response rate
further reported that this regimen was well tolerated, with to single-agent carboplatin was 17/21 (81%; 95% confidence interval
myelosuppression as the most significant toxicity (one-third of patients 59%–93%) and to actinomycin D was 53/59 (90%; 95% confidence inter-
had grade III/IV neutropenia/thrombocytopenia). Etoposide is a semi- val 79%–96%). This suggests that the absolute difference between the
synthetic derivative of podophyllotoxin, used since the 1990s, as a two regimens could be as great as 37% within an accepted range of un-
single-agent [12–16] or in multiagent regimens [17,18] for treatment certainty. In the prior report, however, patients received carboplatin or
of patients with GTN. In general, etoposide has more side effects than actinomycin D according to a risk-adapted algorithm. Patients with hCG
other single-agent chemotherapies and carries a slight increase in life- b 150 IU/L in the first time period of the study and hCG b 300 IU/L in the
time absolute risk of leukemia; despite this it has excellent response second time period of the study received single-agent actinomycin D
rates in the treatment of GTN and remains an important agent [17–19]. while patients with hCG N 300 IU/L were eligible to receive second-
The best chemotherapy regimen for patients with low-risk GTN after line treatment with carboplatin. This leaves open the question as to
failure of MTX/FA is unknown [1], but Act-D, which is widely used all whether carboplatin is non-inferior to actinomycin D among unselected
over the world, tends to be the favored choice [19]. To date there is lim- patients requiring second-line chemotherapy.
ited data exploring alternative options. There is only one paper As reported complete response rates to actinomycin D as second-
reporting the experience with carboplatin [11], and limited experience line chemotherapy for methotrexate resistant low-risk gestational tro-
with the use of etoposide [12–16]. The shortage of Act-D in the phoblastic neoplasia range from 60% to 90% [11,23–26], we performed
Brazilian market necessitated the treatment of our patients with MTX/ our power calculation assuming an average response rate to either
FA-resistant GTN with these less common single-agent chemotherapy second-line regimen of 80%. Based on the Winter, et al. [11] paper, we
regimens. There are no prior Brazilian cohort studies evaluating conservatively posited the null hypothesis of the regimens being simi-
carboplatin or etoposide in the treatment of women with MTX/FA larly efficacious within an absolute range of 30%. For calculating the sta-
chemoresistant low-risk GTN. tistical power of the study, this meant that if there is truly no difference
P.A.R. Mora et al. / Gynecologic Oncology 153 (2019) 277–285 279
between actinomycin D and carboplatin, then 44 patients (at least 22 in of etoposide, MTX/FA, cyclophosphamide, and oncovin (vincristine)
each group) would be required to have 80% power to ensure that the (EM/CO) was administered, i.e. EMA/CO without Act-D, and the pacli-
upper limit of a one-sided 95% confidence interval (or equivalently a taxel, cisplatin and etoposide regimen (TP/TE) was used as a fourth-
90% two-sided confidence interval) would exclude an absolute differ- line regimen.
ence in cure rates in favor of actinomycin D of N30% [27,28]. After hCG normalization, patients received 3 consolidation cycles of
chemotherapy, which was interrupted in case of toxicity, and were
2.4. Diagnosis of GTN monitored monthly with hCG levels for 12 months, when they were
discharged from follow-up [3]. If patients did not attend the scheduled
According to FIGO 2000 criteria, GTN was diagnosed when there was visits, a social worker and hospital psychologist actively tried to contact
a histological diagnosis of choriocarcinoma or when quantitative hCG them by phone, electronic message and telegram to identify what was
serum monitoring exhibited four hCG plateaued values over a period hindering compliance and to motivate them to return to follow-up.
of at least 3 weeks, an increased hCG level in three consecutive mea-
surements or more for at least 2 weeks, or when hCG levels remain ele-
2.6. Outcomes
vated, even if they are falling, 6 months or more from evacuation of a
molar pregnancy [22].
The primary outcome was the occurrence of remission following
second-line chemotherapy (Act-D, carboplatin or etoposide). Secondary
2.5. Staging, risk factors and treatment of GTN
outcomes were toxicity in the various second-line chemotherapy regi-
mens, number of cycles required to attain GTN remission, time to remis-
Patients were staged according to FIGO 2000 GTN anatomical stag-
sion, duration of follow-up, and occurrence of relapse and death.
ing and assigned a prognostic score for resistance to single-agent che-
motherapy following the FIGO/WHO Prognostic Scoring System [24].
Lung metastases were detected using a chest X-ray [1,3,22]. Magnetic 2.7. Variables
resonance imaging of the brain and abdomen were used for patients
with visible pulmonary metastasis on chest X-ray or genital metastasis The following population variables were studied: age (in years),
[1,3,22]. number of gestations and parity of the patient.
Measurement of hCG in all Reference Centers employed the Siemens The following clinical variables of gestational trophoblastic disease
Diagnostic Products Corporation (DPC) Immulite® assay. The reference were evaluated: gestational age at diagnosis (in weeks), occurrence of
value for normal results was an hCG value below 5 IU/L. All patients in- medical complications at the time of diagnosis: anemia (hemoglobin
cluded in this study received contraceptive counseling and received b9 g/dL), vaginal bleeding, enlarged uterus for gestational age (when
hormonal contraception [3]. the uterine size is N4 cm above the expected for fundal height for gesta-
The 8-day MTX/FA regimen with methotrexate 1 mg/kg intramuscu- tional age), theca lutein cysts (presence of ovarian cyst exceeding 6 cm),
lar on days 1, 3, 5, and 7 alternating with folinic acid 0.1 mg/kg orally on preeclampsia (systolic blood pressure levels above 140 mm Hg or dia-
days 2, 4, 6, and 8 was used as first-line treatment in cases of low-risk stolic above 90 mm Hg with proteinuria higher than 300 mg/24 h),
GTN if there was no contraindication [1,3,22]. In cases of MTX/FA resis- hyperemesis (N5 episodes of vomiting per day, with or without meta-
tance and when it was available, second-line chemotherapy was admin- bolic changes), hyperthyroidism (levels of thyroid stimulating hormone
istered with Act-D 1.25 mg/m2 (maximum 2.0 mg) IV pulse every below 0.01 IU/L and free thyroxine above 91.5 ng/dL) and respiratory
2 weeks [1,3,22]. failure.
In periods of Act-D shortage, patients were advised on the available The following pathological variables were evaluated: the histopath-
therapeutic options. After counseling, the treatment choice was dictated ological diagnosis of gestational trophoblastic disease (complete or par-
by patient/physician preference on an individual basis with no formal tial hydatidiform mole or CCA) and the level of hCG at diagnosis of
randomization. Patients were treated with one of the following chemo- gestational trophoblastic disease (IU/L).
therapy regimens: Regarding the clinical aspects of gestational trophoblastic neoplasia,
the following variables were studied: the GTN stage and FIGO/WHO
a. Carboplatin AUC = 6 every 21 days with maximum dose of 900 mg. prognostic score, antecedent pregnancy (molar pregnancy, term/pre-
Dose was calculated using the Calvert formula and Cockcroft-Gault term pregnancy, abortion or ectopic pregnancy), hCG pre-treatment
estimation of GFR, as described by Winter, et al. [11] level (IU/L) and time between the end of antecedent pregnancy and
b. Etoposide, dose of 100 mg/m2, day 1–5, every 14 days [13,14]. the beginning of chemotherapy with MTX/FA.
Considering the GTN therapeutic variables, we evaluated the num-
ber of cycles of MTX/FA administered, the time required to change to
Beginning in 2013, there was a shortage and unavailability of Act-D the second-line treatment (in weeks), the level of hCG at the time of
to treat MTX-resistant low-risk GTN in Brazil, and we used etoposide MTX/FA resistance (IU/L), number of cycles of second-line chemother-
as our second-line therapy in 2013–2014. When we became aware of apy (without consolidation cycles), the type and intensity of toxicity
pre-published favorable results of second-line treatment with of second-line chemotherapy, excluding episodes after remission dur-
carboplatin from the Sheffield Centre for Trophoblastic Disease, we ing consolidation chemotherapy, according to Common Terminology
switched to carboplatin in 2015–2017. Criteria for Adverse Events, Version 5.0, 2017 (CTCAE, 2017) [29], occur-
Treatment was delayed if the patient presented with neutropenia rence of delay and number of days of delay to start a new cycle of che-
(b1000/mm3) or thrombocytopenia (b75,000/mm3) until recovery, motherapy due to toxicity, occurrence of remission with the second-
and the carboplatin dose was reduced to an estimated AUC of 5 line regimen (defined as normalization of hCG levels - lower than
mg/mL/min for subsequent doses [11]. If hematological toxicity caused 5 IU/L – which was maintained for at least 3 weeks), resistance to the
at least one delay in the chemotherapy cycles, granulocyte colony stim- second-line regimen (characterized by hCG plateau of ±10% after
ulating factor was routinely used in the subsequent cycles until remis- 2 cycles of chemotherapy or its re-elevation), toxicity as a reason to
sion of the disease. switch to a third-line regimen (characterized by the occurrence of
In the case of resistance to second-line therapy, severe toxicity grade III/IV toxicity in two consecutive cycles, or by the patient's desire
(grade III or IV in two consecutive cycles) to second-line treatment or after medical advice, after the first episode of grade III/IV toxicity in the
by the patient's desire after medical advice following the first episode second-line regimen), relapse (characterized by the re-elevation of hCG
of grade III/IV toxicity in the second-line treatment, a third-line regimen levels after remission, in the absence of a new pregnancy) and death.
2.8. Statistical analysis with gestational trophoblastic disease (GTD). Among these, 1737
(80.5%) achieved spontaneous remission and 421 (19.5%) developed
To analyze the association between the second-line chemotherapy GTN, among which 377 (89.5%) were categorized as low-risk GTN and
treatments (Act-D, carboplatin or etoposide) and each of the categorical 356 (94.4%) were treated with single-agent MTX/FA. We observed 75
variables, Chi-square test or Fisher's exact test was used when appropriate. (21.1%) patients with MTX/FA resistance, of which 40 (53.3%) were
To compare continuous variables among the second-line chemother- treated with Act-D, 23 (30.7%) with carboplatin and 7 (9.3%) with
apy treatments, the Kruskal-Wallis test was used. A Bonferroni- etoposide.
corrected Mann-Whitney U test was used for pairwise comparisons be- The presenting characteristics of patients with low-risk GTN with
tween two groups in cases of significance by the Kruskal-Wallis test. MTX/FA resistance were similar among the three regimens studied
Differences were considered statistically significant when p-values (Table 1). The different groups of patients treated were comparable,
were b0.05. Statistical analysis was made using R software statistical with no statistical differences in age (p = 0.982), gravidity (p =
package version 3.3.2, available at www.r-project.org. 0.902), parity (p = 0.601), gestational age at the diagnosis (p =
0.872), occurrence of medical complications, histology of GTD (p =
3. Results 0.768) or hCG level pre-evacuation (p = 0.126).
Patients with MTX/FA resistance treated with Act-D, carboplatin or
Fig. 1 represents a flow diagram describing the study population. etoposide similarly did not differ in clinical and therapeutic aspects of
From January 2010 to December 2017, 2158 patients were diagnosed low-risk GTN management (Table 2). They were mainly patients with
Gestational trophoblastic disease

N = 2,158
Spontaneous remission GTN

N = 1,737 (80.5%) N = 421 (19.5%)
Low-risk GTN High-risk GTN

N = 377 (89.5%) N = 44 (10.5%)
Act-D as first line MTX/FA as first line

N = 21 (5.6%) N = 356 (94.4%)
Resistance Toxicity Remission

N = 75 N = 19 N = 262
(21.1%) (5.3%) (73.6%)
EMA/CO Act-D
N = 5 (6.7%) N = 19
Remission 100%
Results of 2nd line chemotherapy with Act-D, carboplatin or etoposide
following primary MTX/FA resistance in low-risk GTN
Act-D Carboplatin Etoposide

N = 40 N = 23 N=7
(53.3%) (30.7%) (9.3%)
Resistance Toxicity Remission Resistance Toxicity Remission Resistance Toxicity Remission

N=8 N=0 N = 32 N=9 N=3 N = 11 N=2 N=0 N=5
(20%) (80%) (39.1%) (13%) (47.8%) (28.6%) (71.4%)
EMA/CO EM/CO EM/CO

N=8 N = 12 N=2
Remission 100% Remission N = 9 (75%) Remission N = 1 (50%)
Resistance N = 3 (25%) Resistance N = 1 (50%)
TP/TE TP/TE
N=3 N=1
Remission 100% Remission 100%
Fig. 1. Flow diagram summarizing the derivation of the study population. GTN – gestational trophoblastic neoplasia. MTX/FA – methotrexate/folinic acid. Act-D – Actinomycin-d. EMA/CO –
etoposide, methotrexate, actinomycin D/cyclophosphamide, oncovin (vincristine). EM/CO - etoposide, methotrexate/cyclophosphamide, oncovin (vincristine). TP/TE – paclitaxel,
cisplatin/paclitaxel, etoposide.
Table 1
Characteristics of patients with low-risk gestational trophoblastic neoplasia after MTX/FA resistance according to the second-line regimen.
Variables Actinomycin-D Carboplatin Etoposide p-Value

N = 40 N = 23 N=7
Age (years)a 25 (21–36) 25 (21–34) 29 (21−31) 0.982 K

Graviditya 1 (1–2) 1 (1–2) 1 (1–2) 0.902 K
Paritya 0 (0–1) 0 (0–0.5) 0 (0–1) 0.601 K
Gestational age at diagnosis (weeks)a 10 (9–11) 10 (9–11) 9 (9–11) 0.872 K
Medical complication at presentation, n (%)
Vaginal bleeding 23 (57.5%) 14 (60.9%) 3 (42.8%) 0.774 C
Anemia 5 (12.5%) 5 (21.7%) 2 (28.6%) 0.370 C
Enlarged uterus for gestational age 23 (57.5%) 14 (60.9%) 3 (42.8%) 0.774 C
Theca lutein cysts 5 (12.5%) 5 (21.7%) 2 (28.6%) 0.370 C
Hyperemesis 9 (22.5%) 4 (17.4%) 2 (28.6%) 0.687 C
Hyperthyroidism 2 (5%) 0 0 0.619 C
Respiratory distress syndrome 2 (5%) 0 0 0.619 C
Histology of GTDb, n (%) 0.768 C
Complete hydatidiform mole 30 (75%) 19 (82.6%) 5 (71.4%)
Partial hydatidiform mole 5 (12.5%) 3 (13%) 1 (14.3%)
Choriocarcinoma 5 (12.5%) 1 (4.4%) 1 (14.3%)
hCGc (IU/L) at molar evacuationa 175,000 (150000–212,500) 150,000 (115000–200,000) 150,000 (130000–265,000) 0.126 K
C – Chi-square test.
K – Kruskal-Wallis test.
a
Median and interquartile range.
b
GTD – gestational trophoblastic disease.
c
hCG – human chorionic gonadotropin (IU/L – International units per liter).
non-metastatic GTN (p = 0.952) following molar pregnancies (p = was significantly different among the studied groups (p = 0.002): with
0.456) with low WHO/FIGO Prognostic Risk Scores (p = 0.818) and more cycles of Act-D needed compared to carboplatin (p = 0.016) or
moderately elevated hCG values upon initiating primary therapy (p = etoposide (p = 0.027), while there was no difference between the num-
0.989). Most patients started chemotherapy within 4 months of preg- ber of cycles of carboplatin and etoposide required to induce remission
nancy termination (p = 0.729) and experienced resistance after about (p = 0.479). The total number of cycles administered of Act-D,
5 cycles (p = 0.785). hCG levels were similar among the three groups carboplatin and etoposide were 203, 56 and 23, respectively. There
at the time of switching to a second-line regimen: 7890, 1385 and was a significant increase in the occurrence of chemoresistance/toxicity
4250 IU/L (p = 0.188), respectively. among patients treated with carboplatin (52.2%) than in patients re-
Comparing the remission rates among the three second-line regi- ceiving Act-D (20%, p = 0.008) or etoposide (28.5%, p = 0.022). It was
mens, Act-D (80%) and etoposide (71.4%, p = 0.659) were similar, but also observed that only 29% of the patients treated with carboplatin re-
both were higher than carboplatin (47.8%, p = 0.033 and p = 0.025, received the chemotherapy cycles without delay, which was significantly
spectively) (Table 3). The number of cycles needed to achieve remission different when compared to the women treated with Act-D (98%, p b
Table 2
Clinical and therapeutic profile of patients with MTX/FA failure for treatment of low-risk gestational trophoblastic neoplasia according to the second-line regimen.

N = 40 N = 23 N=7
Stage, n (%) 0.952 C

I 35 (87.5%) 19 (82.6%) 6 (85.7)
II 1 (2.5%) 1 (4.3%) 0
III 4 (10%) 3 (13.1%) 1 (14.3%)
IV 0 0 0
WHO/FIGOb Prognostic Risk Score, n (%) 0.995 C
0 1 (2.5%) 0 0
1 11 (27.5%) 6 (26.1%) 1 (14.3%)
2 8 (20.0%) 5 (21.7%) 2 (28.5%)
3 6 (15.0%) 5 (21.7%) 1 (14.3%)
4 5 (12.5%) 2 (8.7%) 1 (14.3%)
5 4 (10%) 2 (8.7%) 1 (14.3%)
6 5 (12.5%) 3 (13.1%) 1 (14.3%)
WHO/FIGOb Prognostic Risk Scorea 2 (1–4) 3 (1–4) 3 (2–4) 0.818 K
Antecedent of pregnancy, n (%) 0.456 C
Hydatidiform mole 35 (87.5%) 22 (95.6%) 6 (85.7%)
Term/preterm 4 (10%) 0 (0%) 1 (14.3%)
Abortion 1 (2.5%) 1 (4.4%) 0 (0%)
hCGc (IU/L) at initial MTX/FAd treatmenta 14,000 (883.5–89,250) 13,000 (4800–34,000) 12,000 (1550–30,900) 0.989 K
Time between molar evacuation and initial MTX/FAd treatmenta (months) 4 (3–5) 4 (3–5) 4 (3–4) 0.729 K
Number of cycles of MTX/FAd treatmenta 5 (4–7) 5 (4–5) 5 (4–6) 0.785 K
Time to switch to second-line therapy (weeks)a 10 (8–14) 10 (8–11) 10 (8–12) 0.785 K
hCGc (IU/L) at switch to second-line therapya 7890 (2568–9870) 1385 (443–6824) 4250 (2580–5920) 0.188 K
a
b
WHO/FIGO – World Health Organization/International Federation of Gynecology and Obstetrics.
c
d
MTX/FA – Methotrexate with folinic acid rescue.
Table 3
Outcomes of second-line regimen for treatment of patients with low-risk gestational trophoblastic neoplasia after MTX/FA failure.

N = 40 N = 23 N=7
Among all three Pairwise comparisons
regimens
Actinomycin-D Actinomycin-D Carboplatin
versus versus versus
Carboplatin Etoposide Etoposide
Remission in second line, n (%) 32 (80%) 11 (47.8%) 5 (71.4%) 0.047 C 0.033 F 0.659 F 0.025 F
95% CIc: 65%–90% 95% CIc: 95% CIc:
29%–67% 35%–92%
Number of cycles needed to remission in 3 (3–6) 3 (2–3) 2 (1–3) 0.002 K 0.016 M 0.027 M 0.479 M
second-linea,b
Number of cycles to remissionb 6 (6–7) 5 (5–5.5) 4 (4–5) 0.003 K 0.003 M 0.014 M 0.748 M
Time to switch to third-line therapy (weeks)b 12 (10–14) 11 (9–13) 8 (7–10) 0.231 K
hCG (IU/L)d at switch to third-line therapy 1035 900 899 0.507 K
(262.5–21,695) (220–3640) (88.5–4200)
Reason to switch to third-line therapy
Chemoresistance/toxicity, n (%) 8 (20%) 12 (52.2%) 2 (28.6) 0.022 C 0,008 F 0,609 F 0,022 F
Chemotherapy cycles on time, n (%) 39 (98%) 7 (29%) 6 (85%) b0.001 C b0.001 F 0.154 F 0.009 F
Number of days overdueb 4 (1–5) 8 (5–18) 5 (2–6) 0.001 K 0.001 M 0.051 M 0.892 M
Number of patients that needed G-CSFe, n (%) 0 9 (39%) 2 (29%) b0.001 K b0.001 F 0.019 F 0.204 F
Time to remission (weeks)b 20 (15–26) 20 (15–23) 12 (9–18) 0.099 K
Duration of follow up (months)b 16 (15–19) 17 (15–18) 15 (13–16) 0.081 K
Relapse, n (%) 0 0 0
Death, n (%) 0 0 0
F – Fisher's exact test.
M – Bonferroni-corrected Mann-Whitney U test.
a
Without consolidation.
b
c
CI – confidence interval.
d
e
G-CSF – granulocyte-colony stimulating factor.
0.001) or etoposide (85%, p = 0.009). Among patients treated with Act- treatment [1], the expectation is that most women can still be cured
D, 5 (2.4%) cycles required delay, whereas among patients treated with with a second-line single-agent chemotherapy, thereby avoiding
carboplatin and etoposide this occurred in 39 (69.6%) and 4 (17.4%) cy- multiple-agent treatment and its attendant early and late toxicities
cles, respectively. The length of delay was significantly higher in pa- [1,25,30]. In this study, we have shown that carboplatin had a lower re-
tients treated with carboplatin (median of 8 days, p = 0.001) or mission rate than Act-D and etoposide as a second-line regimen for low-
etoposide (median of 5 days, p = 0.051) when compared to those risk GTN after MTX/FA resistance. Carboplatin had a higher occurrence
treated with Act-D (median of 4 days). of chemotherapy failure and a higher rate of grade III/IV toxicities, nota-
The significant delays between the carboplatin cycles occurred due bly with hematological impairment. Although patients receiving
to treatment toxicity. Table 4 shows that only patients treated with carboplatin required more support with G-CSF than those treated with
carboplatin had grade III/IV toxicity. Patients treated with carboplatin Act-D, N2/3 of patients on carboplatin experienced delayed cycles of che-
had significantly more hematological toxicity, notably anemia (30.4%, motherapy, postponing the continuity of treatment when compared to
p = 0.008), lymphopenia (47.7%, p b 0.001) and thrombocytopenia patients treated with Act-D.
(43.4%, p b 0.001), as well as a higher occurrence of febrile neutropenia The only prior study evaluating the response to second-line treat-
(14.4%, p = 0.044) and vomiting (60.9%, p b 0.001) than those treated ment of patients with low-risk GTN after MTX/FA resistance found sim-
with Act-D (5%, none, 2.5%, none, 10%, respectively). Alopecia was signif- ilar remission rates in women treated with Act-D and carboplatin (53/
icantly reported among patients treated with etoposide (100%, p b 59–89.8% versus 17/21–80.9%, respectively) [11], higher rates than we
0.001), being uncommon among patients treated with Act-D (5%) or observed in our study. Population characteristics such as race and eth-
carboplatin (4.3%). Due to toxicity, 27 (48.2%) cycles of carboplatin nicity have been cited to explain different responses and toxicity to che-
were administered at a dose reduction of AUC5. motherapy treatments with carboplatin and other agents [31,32]. It is
Compared to patients treated with Act-D, the number of women possible that differences in patient population may partly explain differ-
treated with carboplatin (39%, p b 0.001) or etoposide (29%, p = ences in outcomes between the experience with Winter et al. [11] and
0.019) who required G-CSF treatment was significantly higher our data. It should also be noted that in the study by Winter et al. [11],
(Table 3). All patients who did not respond to the second-line regimen hCG levels at the time of the switch to the second-line therapy had
were successfully treated with multi-agent chemotherapy, as shown lower median and interquartile levels between patients who were
in Fig. 1, and there were no cases of relapse or death among patients treated with Act-D than among women who were treated with
studied. carboplatin (28, interquartile: 18–69 IU/L versus 2126, interquartile:
1149–7948 IU/L, respectively). In our study, patients with low-risk
GTN after MTX/FA resistance, who were treated with different second-
4. Discussion line regimens, were comparable in variables commonly associated
with response to chemotherapy, such as age, hCG level at the time of
While most patients with low-risk GTN achieve remission with failure of first-line chemotherapy, histology of GTD, antecedent preg-
single-agent chemotherapy [19], our study showed that 21% of patients nancy, the interval between the end of previous pregnancy and the be-
needed a second-line regimen, similar to prior studies [19,24–26,30]. ginning of MTX/FA chemotherapy, presence of metastatic disease and
Although there is no consensus regarding the best second-line GTN FIGO/WHO score [25,33,34].
Table 4
Adverse events due to second-line regimen for treatment of low-risk gestational trophoblastic neoplasia after MTX/FA resistance, graded according to Common Terminology Criteria for Adverse Events, version 5.0 (2017).
Variable Actinomycin-D (N = 40) Carboplatin (N = 23) Etoposide (N = 7) Among all three regimens Pairwise comparisons
p-value p-Value
Disorders by system Adverse event N (%) CTC grade (N/%) Adverse event CTC grade (N/%) Adverse event CTC grade (N/%)
(Chi-square test) (Fisher's exact test)
N (%) N (%)
1 2 1 2 3 4 1 2 Actinomycin-D Actinomycin-D Carboplatin
versus versus versus
Carboplatin Etoposide Etoposide
Blood
4 (19.4) 1 (4.3) – 1 (14.3) –
P.A.R. Mora et al. / Gynecologic Oncology 153 (2019) 277–285

Anemia 2 (5) 1 (2.5) 1 (2.5) 7 (30.4) 2 (8.7) 1 (14.3) 0.018 0.008 0.390 0.637
Febrile neutropenia – – – 4 (14.4) – – 3 (13) 1 (4.3) 1 (14.3) 1 (14.3) – 0.031 0.044 0.148 1
Gastrointestinal
Diarrhea 10 (25) 6 (15) 4 (10) 5 (21.7) 5 (21.7) – – – 1 (14.3) 1 (14.3) – 1
Mucositis oral 14 (35) 10 (25) 4 (10) 7 (30.4) 3 (13) 4 (17.4) – – 1 (14.3) 1 (14.3) – 0.650
Nausea 18 (45) 18 (45) – 20 (87) 12 (52.2) 8 (34.8) – – 2 (28.6) 2 (28.6) – b0.001 0.001 0.681 0.006
Stomach pain 5 (12.5) 4 (10) 1 (2.5) 7 (30.4) 4 (17.4) 3 (13) – – 1 (14.3) 1 (14.3) – 0.1702
Vomiting 4 (10) 4 (10) – 14 (60.9) 8 (34.8) 6 (26.1) – – 2 (28.6) 2 (28.6) – b0.001 b0.001 0.213 0.204
Infections
Upper respiratory 3 (7.5) 3 (7.5) – 3 (13) 3 (13) – – – 1 (14.3) 1 (14.3) – 0.5911
Urinary tract 2 (5) 2 (5) – 5 (21.7) 4 (17.4) 1 (4.3) – – – – – 0.0864
Vaginal 4 (10) 4 (10) – 5 (21.7) 4 (17.4) 1 (4.3) – – 1 (14.3) 1 (14.3) – 0.4076
Investigations
ALT ↑ 1 (2.5) 1 (2.5) – 11 (47.7) 3 (13) 5 (21.7) 3 (13) – 1 (14.3) 1 (14.3) – b0.001 b0.001 0.278 0.193
AP ↑ 1 (2.5) 1 (2.5) – 9 (39.1) 2 (8.7) 4 (17.4) 3 (13) – 1 (14.3) 1 (14.3) – b0.001 b0.001 0.278 0.371
AST ↑ 1 (2.5) 1 (2.5) – 9 (39.1) 2 (8.7) 4 (17.4) 3 (13) – 1 (14.3) 1 (14.3) – b0.001 b0.001 0.278 0.371
Lymphocyte count ↓ – – – 11 (47.7) 4 (17.4) 4 (17.4) 3 (13) 1 (4.3) 1 (14.3) 1 (14.3) – b0.001 b0.001 0.148 0.030
Neutrophil count ↓ 1 (2.5) – 1 (2.5) 13 (56.5) 5 (21.7) 5 (21.7) 3 (13) 1 (4.3) 2 (28.6) 1 (14.3) 1 (14.3) b0.001 b0.001 0.002 0.181
Platelet count ↓ 1 (2.5) – 1 (2.5) 10 (43.4) 3 (13) 3 (13) 3 (13) 1 (4.3) 1 (14.3) 1 (14.3) – b0.001 b0.001 0.148 0.024
Reproductive
Irregular menstruation 1 (2.5) 1 (2.5) – 3 (13) 3 (13) – – – – – – 0.300
Menorrhagia 2 (5) 2 (5) – 4 (17.4) 4 (17.4) – – – 1 (14.3) 1 (14.3) – 0.210
Skin
Alopecia 2 (5) 2 (5) – 1 (4.3) 1 (4.3) – – – 7 (100) 5 (71.4) 2 (28.6) b0.001 0.528 b0.001 b0.001
Vascular
Phlebitis 2 (5) 2 (5) – 1 (4.3) 1 (4.3) – – – 1 (14.3) 1 (14.3) – 0.5369
ALT – Alanine aminotransferases. AP – Alkaline phosphatase. AST – Aspartate aminotransferases.

G-CSF – Granulocyte-colony stimulating factor.
283
There was a higher occurrence of chemoresistance/toxicity among this study, we should highlight that the shortage of Act-D compromises
women receiving carboplatin in our series. Winter et al. [11] reported not only the treatment of women with failure of first-line MTX/FA treat-
a grade III/IV toxicity of neutropenia (38.1%) and thrombocytopenia ment for low-risk GTN, but will directly affect the treatment of patients
(28.6%), similar to our results, which identified bone marrow suppres- who do not respond to the second-line treatment and need multiagent
sion as the main toxicity among patients treated with carboplatin. This regimen, such as EMA/CO [1,19].
led to a delay in 71.4% of patients receiving carboplatin, identical to In conclusion, carboplatin as a chemotherapeutic drug used to treat
our results. However, although Winter et al. [11] did not report the Brazilian women with low-risk GTN after MTX/FA resistance during
time needed to restart chemotherapy, this was significantly higher the shortage of Act-D, did not have a satisfactory clinical response rate,
among our patients treated with carboplatin (median of 8 days). The likely due to severe hematological adverse effects, which postponed
delay between carboplatin cycles due to toxicity may have contributed chemotherapy cycles. Patients treated with Act-D had an excellent clin-
to the increased resistance rates observed among these patients [35]. ical response compared to those treated with carboplatin, without the
We agree with Winter et al. [11], that carboplatin doses may be side effects observed with carboplatin and etoposide. In the absence of
overestimated by 30% due to possible over-estimation of renal clearance more robust evidence to define the best treatment for women with
using the Cockcroft-Gault formula based on serum creatinine, and this low-risk GTN after MTX/FA resistance, it is reasonable for clinicians to
could be related to the toxic effects observed. Likewise, it may be neces- rely on Act-D. It is imperative for both governmental and professional
sary to consider the use of prophylactic G-CSF in patients requiring medical organizations to use their full influence to reduce the occur-
carboplatin or to initiate its use early in order to avoid the delay of cycles rence of global shortages of life-saving chemotherapy agents.
with this regimen and possible chemoresistance.
Although etoposide attained excellent remission rates in patients
Author contribution
with low-risk GTN after MTX/FA resistance, similar to those treated
with Act-D, and with fewer cycles of chemotherapy, it has been shown
AB, KME, NSH and RSB conceived the study. AB, GCV, APVSE, KME,
to be more toxic, presenting more alopecia and neutropenia. The use
NSH and RSB designed the study. APVSE was responsible for the ethical
of etoposide is also associated with risk of secondary malignancies, in-
requirements during the design and execution of the study. PARM, AB,
cluding leukemia, breast and colon cancer and melanoma [36].
JRF, SYS and EHU treated all patients studied. PARM collected data,
Our study does have several limitations. The main limitation of this
audited by AB and JRF (data from Rio de Janeiro Federal University),
study is the small number of patients having MTX/FA resistance as
SYS (data from Universidade Federal de São Paulo) and EHU (data
first-line therapy in low-risk GTN. Only 21% of patients with low-risk
from Irmandade da Santa Casa da Misericórdia Hospital). GCV and
GTN developed resistance to MTX/FA. Subdividing such a small cohort
KME were responsible for the sample size calculation and statistical
into different groups leads to wide confidence intervals in estimates of
analysis. All authors contributed to data analysis, interpretation and
response rates. This was particularly true for evaluating etoposide.
wrote the paper, approving the final version.
However, while we considered that differences between this study
and the report from Sheffield could fall within the range of statistical
variation, nonetheless the absolute difference in response rates be- Conflict of interests
tween carboplatin and Act-D exceeded our very conservative criteria
for assuming equivalent efficacy, suggesting that sample size alone is The authors declare no conflict of interests.
unlikely to be the source of variation. Data was also collected from dif-
ferent hospital databases and may not reflect the Brazilian general pop-
ulation. As referral centers, these data may overestimate the true Funding
prevalence of MTX/FA resistance, attracting patients with a worse prog-
nosis to respond to treatment with single-agent chemotherapy. Due to This research was supported by the Donald P. Goldstein MD Tropho-
the retrospective nature of this study, it is important to highlight that blastic Tumor Registry Endowment (KME, NH, RSB) and the Dyett Fam-
adverse events for the different regimens were identified through med- ily Trophoblastic Disease Research and Registry Endowment (KME, NH,
ical record review, rather than in real time, which could introduce ascer- RSB). The funding agencies had no direct role in the generation of the
tainment bias or be incomplete. Although well-established criteria were data or manuscript.
followed when discontinuing a chemotherapeutic regimen due to toxic-
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Gynecologic Oncology 156 (2020) 598–605
Contents lists available at ScienceDirect
Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno
Comparison of treatment for low-risk GTN with standard 8-day MTX/FA

regimen versus modified MTX/FA regimen without chemotherapy on
the weekend
Antonio Braga a,b,c,⁎, Clymene de Souza Hartung Araújo a,b, Paulo Alexandre Ribeiro Mora a,c,d, Eduardo Paulino d,
Andréia Cristina de Melo d, Guillermo Coca Velarde c, Ana Paula Vieira dos Santos Esteves a,b,
Joffre Amim Junior a,b, Jorge Rezende Filho a,b, Kevin M. Elias e, Neil S. Horowitz e, Ross S. Berkowitz e
a
Rio de Janeiro Trophoblastic Disease Center (Maternity School of Rio de Janeiro Federal University, Antonio Pedro University Hospital of Fluminense Federal University), Rio de Janeiro, RJ, Brazil
b
Postgraduate Program in Perinatal Health, Faculty of Medicine, Maternity School of Rio de Janeiro Federal University, Brazil
c
Postgraduate Program in Medical Sciences, Fluminense Federal University, Niterói, RJ, Brazil
d
Brazilian National Cancer Institute, Hospital do Câncer 2, Rio de Janeiro, RJ, Brazil
e
New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical
School, Boston, MA, USA
H I G H L I G H T S
• Low-risk GTN didn’t appear to have compromised oncologic outcomes when treated with modified 8-day MTX/FA.
• Modified 8-day MTX/FA didn’t appear to increase chemoresistance, number of chemotherapy cycles to achieve remission or toxicity.
• When treatment on weekends isn’t an option, the modified 8-day MTX/FA appears to be an acceptable alternative.
a r t i c l e i n f o a b s t r a c t
Article history: Objective. To compare the outcomes of patients with low-risk gestational trophoblastic neoplasia (GTN)
Received 11 November 2019 treated with standard 8-day methotrexate/folinic acid (MTX/FA) versus modified regimen.
Received in revised form 21 December 2019 Methods. Retrospective cohort study of patients with low-risk GTN followed at Rio de Janeiro Federal Univer-
Accepted 29 December 2019
sity, from January/1990-December/2017 with standard 8-day MTX/FA or modified regimen (MTX administered
Available online 10 January 2020
on the 8th day rather than 7th) to avoid treatment on the weekend.
Keywords:
Results. From 937 patients with low-risk GTN, 538 were treated with standard MTX/FA and 98 patients re-
Gestational trophoblastic neoplasia ceived modified regimen. Both groups were comparable in age (p = .749), antecedent pregnancy (p = .221),
Chemotherapy time to initiate chemotherapy (p = .926), hCG pretreatment level (p = .112) and WHO/FIGO prognostic risk
Methotrexate score (p = .723). Patients treated with modified MTX/FA had twice of cases of metastatic lung disease compared
Methotrexate-resistance with the standard regimen (22.5% vs 10.6%; p = .002). The rate of remission (p = .999), number of cycles to re-
mission 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 b .001) when com-
pared with the standard regimen, these variables showed no significant differences after multivariate logistic re-
gression 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.
© 2020 Elsevier Inc. All rights reserved.
1. Introduction
⁎ Corresponding author at: Maternidade Escola, Universidade Federal do Rio de Janeiro,
Rua Laranjeiras, 180, Laranjeiras, Rio de Janeiro, RJ 22240-003, Brazil. Gestational trophoblastic neoplasia (GTN) encompasses various
E-mail address: antonio.braga@ufrj.br (A. Braga). neoplastic trophoblastic lesions, comprising invasive mole,
0090-8258/© 2020 Elsevier Inc. All rights reserved.
A. Braga et al. / Gynecologic Oncology 156 (2020) 598–605 599
choriocarcinoma (CCA), placental site trophoblastic tumor (PSTT) and 2. Material and methods
epithelioid trophoblastic tumor (ETT). Since Li et al. [1] reported the
sensitivity of gestational trophoblastic neoplasia (GTN) to methotrexate 2.1. Study design
(MTX), most of these tumors became curable without the need for sur-
gery [2]. This is a retrospective cohort study of patients with low-risk GTN
MTX irreversibly binds to the enzyme dihydrofolate reductase, followed at the Rio de Janeiro Trophoblastic Disease Center – Maternity
preventing the formation of tetrahydrofolate, active form of folic acid, School of Rio de Janeiro Federal University (Rio de Janeiro – RJ, Brazil,
that acts as a cofactor for thymidylate synthetase, which is fundamental data entered by CSHA and audited by AB), from January 1990 to Decem-
in cell replication, notably the S phase of the cell cycle. MTX causes rapid ber 2017. This study was approved by the local Institutional Review
disruption of DNA synthesis, promoting cell death, resulting in the re- Board associated with the Brazilian Research Ethics Committee of the
duction of the sensitive serum tumor marker, human chorionic gonad- Maternity School of the Rio de Janeiro Federal University (CAAE
otrophin (hCG), as well as tumor disappearance and consequent 16365019.1.0000.5275 and 16365019.1.0000.5275).
clinical improvement.
More than a half century after the seminal publication of the excep- 2.2. Study participants
tional antineoplastic results of MTX, there is no established best regi-
men of this drug for GTN treatment, and the numerous schemes All patients with low-risk GTN treated with modified or standard 8-
proposed suggest that this issue is still under discussion and unresolved day MTX/FA were included. All cases of molar pregnancy that developed
[3]. GTN or choriocarcinoma had their diagnosis confirmed by the Pathology
Monitoring the balance between the toxicity and the therapeutic Department of the Reference Center. All patients were followed for at
effects of MTX, Bagshawe established postulates that guide the design least 12 months after remission with rigorous contraception program
of MTX regimens for GTN treatment: low doses MTX are effective; [18]. Patients diagnosed with high-risk GTN, PSTT and ETT, and those
folinic acid may increase the tolerability of the treatment and intervals initially treated outside the GTN-RC or received Actinomycin-D (Act-
between cycles are desirable to minimize toxicity but should be as D) as first line treatment for low-risk GTN were excluded. Additionally,
short as possible to avoid drug resistance [4,5]. Considering these prin- patients who were pregnant b12 months after the end of chemother-
ciples, the 8-day regimen that alternates intramuscular MTX (50 mg apy, who were lost to follow-up with b12 months after remission or
fixed dose or 1 mg/kg on days 1, 3, 5 and 7) with oral folinic acid those patients who were treated with 8-day MTX 50 mg fixed dose reg-
(FA) (15 mg fixed dose or 0.1 mg/kg on days 2, 4, 6 and 8) has been im- imen were also excluded [7].
plemented around the world [6–8]. A recent comparison of fixed as op-
posed to adjusted dose MTX/FA has suggested no significant 2.3. Diagnosis of GTN
differences in remission rate and outcomes in an Italian population
[9]. In Brazil we have favored the adjusted dose mostly as the first According to FIGO 2000 criteria, GTN was diagnosed when there was
choice for low-risk GTN patients in all GTN Reference Centers (GTN- a histological diagnosis of choriocarcinoma or when quantitative hCG
RC) [10]. serum monitoring exhibited four hCG plateaued values over a period
However, since the 8-day MTX/FA regimen necessarily includes a of at least 3 weeks, an increased hCG level in three consecutive mea-
day of MTX treatment on the weekend, we have observed that some surements or more for at least 2 weeks, or when hCG levels remain ele-
Brazilian clinicians have utilized a modified MTX/FA regimen, which vated, even if they are falling, 6 months or more from evacuation of a
eliminated MTX administration during the weekend, postponing it to molar pregnancy [19].
Monday. This is basically due to two distinct reasons, depending on
where the patient receives chemotherapy. When patients are treated 2.4. Staging, risk factors and treatment of GTN
fully in the GTN-RC, this situation occurs due to scheduling problems
in the clinical oncology unit, determined by vacations, holidays or by Patients were staged according to FIGO 2000 GTN anatomical stag-
generally limited weekend staff. This scenario occurs more commonly ing and assigned a prognostic score for resistance to single-agent che-
when patients with GTN receive chemotherapy in private clinical oncol- motherapy following the FIGO/WHO Prognostic Scoring System [19].
ogy practices, which do not ordinarily offer treatment on the weekends. Lung metastases were detected using a chest X-ray [7,19]. Magnetic res-
The convenience in administering 5-day MTX (0.4 mg/kg/day, at a onance imaging of the brain and abdomen and chest CT scan were used
maximum of 25 mg/day, without FA rescue), applied from Monday to for patients with visible or suspected pulmonary metastasis on chest X-
Friday, has motivated GTN-RC to adopt this treatment for low-risk ray or genital metastasis. [7,19]. Lung metastasis images were reviewed
GTN [11–14]. While 5-day MTX seems to have similar clinical response centralized in the Reference Center and counted from metastatic nod-
as the 8-day MTX/FA regimen, some studies have reported more toxic- ules larger than 1 cm [7].
ity with 5-day MTX regimens without FA rescue as compared to 8-day During the entire cohort study, we used the Siemens Diagnostic
regimens [10,15,16]. Products Corporation (DPC) Immulite® assay, with the reference
The best chemotherapy regimen for patients with low-risk GTN is value for normal serum hCG results below 5 IU/L.
unknown [17], but 8-day MTX/FA is a common choice globally The standard 8-day MTX-FA regimen consisting of MTX at
[6,7,17]. However, as far as we know, there is no study evaluating the ef- 1 mg/kg intramuscularly on days 1, 3, 5 and 7 alternating with FA
ficacy of the modified 8-day MTX/FA regimen in which MTX is adminis- at 0.1 mg/kg or 15 mg orally on days 2, 4, 6 and 8 was used as first-
tered on day 8 rather than on day 7 thus avoiding treatment during the line treatment in cases of low-risk GTN if there was no contraindica-
weekend. It is unknown whether this change in the timing of chemo- tion [7,19]. Before 2013, FA was regularly administered orally at
therapy administration would lead to an increased number of chemo- 0.1 mg/kg and patients were often instructed to break tablets into
therapy cycles to achieve remission or even a higher development of pieces to use the correct dose as closely as possible. However, after
chemoresistance. 2013, we administered FA orally at a 15 mg fixed dose, regardless
This study describes the results of treatment of Brazilian patients of patient weight, for more convenience, following the European So-
with low-risk GTN with modified 8-day MTX/FA compared to the stan- ciety of Medical Oncology GTD Guideline [7]. In exceptional cases,
dard regimen. This study may be important for settings where oncology where it was not possible to schedule standard 8-day MTX/FA treat-
services have difficulty administering chemotherapy over the weekend, ment during the weekend, or in cases where patients were treated in
and despite that, clinicians maintain the decision to perform the 8-day private clinical oncology clinics, that are unable to administer che-
MTX/FA treatment. motherapy on the weekends, MTX was not administered in the 7th
600 A. Braga et al. / Gynecologic Oncology 156 (2020) 598–605
day, but postponed to the 8th day, avoiding treatment during the 2.5. Outcomes
weekend. The patients were informed about the nature of the modi-
fied treatment and its alternatives and formalized the informed con- The primary outcome was the occurrence of remission following 8-
sent for the chosen treatment. To minimize the potential effect of day MTX/FA. Secondary outcomes were toxicity in the standard and
this delay, treatment with MTX was done at the end of the day, gen- modified 8-day MTX/FA regimen, number of cycles required to attain
erally at 4:00 p.m. on days 1, 3, 5, and then at 8:00 am on day 8, thus GTN remission, time to remission and occurrence of relapse and death.
resulting in an approximate 16 h delay in administration of the last
dose of MTX. Similarly, FA on day 9 was given 24 h after administra- 2.6. Variables
tion of the last MTX of the cycle.
In cases of MTX/FA resistance, second-line chemotherapy was ad- The following population variables were studied: age (in years),
ministered with single agent (Act-D 1.25 mg/m2, maximum 2.0 mg, number of gestations and parity of the patient.
IV pulse every 2 weeks or Carboplatin AUC = 6 every 21 days with Regarding the clinical aspects of gestational trophoblastic neoplasia,
maximum dose of 900 mg or Etoposide, dose of 100 mg/m2 , day the following variables were studied: the antecedent pregnancy (molar
1–5, every 14 days) [20] or multiagent regimen (etoposide, MTX/ pregnancy, term/preterm pregnancy, abortion or ectopic pregnancy),
FA, Act-D, cyclophosphamide, and oncovin (vincristine) – EMA/CO time between the end of antecedent pregnancy and the beginning of
regimen, with or without Act-D, during shortages of Act-D) chemotherapy with 8-day MTX/FA, hCG pre-treatment level (IU/L),
[7,10,20]. the GTN stage and FIGO/WHO prognostic score [19].
After hCG normalization, patients received 3 consolidation cycles of The following pathological variables were evaluated: the histopath-
chemotherapy, and were monitored monthly with hCG serum levels for ological diagnosis of gestational trophoblastic disease (complete or par-
12 months, when they were discharged from follow-up [7,10]. tial hydatidiform mole, invasive mole or CCA).
Fig. 1. Flow diagram summarizing the derivation of the study population. GTN – gestational trophoblastic neoplasia. RC – reference center. MTX/FA – methotrexate / folinic acid. Act-D –
Actinomycin-D.
Considering the GTN therapeutic variables, we evaluated the occur- No difference was observed in the occurrence of remission among
rence of remission, the number of cycles of MTX/FA needed to attain re- patients with low-risk GTN treated with standard 8-day MTX/FA versus
mission or done before resistance, the type and intensity of toxicity of modified 8-day MTX/AF regimen (76.7% × 77.6%; p = .999). Table 3
first-line chemotherapy, excluding episodes after remission during con- showed that treatment with modified 8-day MTX/FA did not increase
solidation chemotherapy, according to Common Terminology Criteria the number of cycles needed to achieve remission in the first-line (5.0
for Adverse Events, Version 5.0, 2017 (CTCAE, 2017) [21], the time re- versus 5.0 cycles; p = .966) or postpone the switch to second-line ther-
quired to change to the second-line treatment (in weeks), reason to apy (10 versus 10 weeks; p = .176). Likewise, no increased
switch to second-line therapy, the level of hCG at the time of MTX/FA re- chemoresistance was observed among patients initially treated with
sistance (IU/L), occurrence of remission with the second-line regimen, modified 8-day MTX/FA when compared to standard 8-day MTX/AF
number of cycles of second-line chemotherapy (without consolidation (90.9% x 90.5%, p = .500). The two 8-day MTX/FA regimens did not dif-
cycles), total number of cycles to remission, time to remission fer significantly in predisposing patients to an increased need for
(weeks), occurrence of relapse or death. multiagent chemotherapy (p = .084), occurrence of relapse (p =
Remission was defined as normalization of hCG levels - lower than .122) or death (p = .475). However, in patients needing second-line
5 IU/L – which was maintained for at least 4 weeks [6]. Resistance was chemotherapy and receiving modified 8-day MTX/FA, they required a
characterized by hCG plateau of ±10% after 2 cycles of chemotherapy higher total number of remission cycles (6 versus 5 cycles; p = .004),
or its re-elevation. Toxicity as a reason to switch to a second-line regi- as well as longer time to achieve remission (19 versus 16 weeks;
men was attained by the occurrence of grade III/IV toxicity in two con- p b 0. 001) compared to patients treated with standard 8-day MTX/FA.
secutive cycles, or by the patient's desire after medical advice, after the Still, when these variables were analyzed excluding the effect of lung
first episode of grade III/IV toxicity in the first-line regimen. Relapse was metastasis occurrence through multivariate logistic regression, it can be
diagnosed by the re-elevation of hCG levels after remission, in the ab- observed that the odds ratio for patients treated with modified 8-day
sence of a new pregnancy. MTX/FA receiving N5 cycles of chemotherapy to achieve remission in
the treatment of second-line chemotherapy was 0.81 (CI 95%:
2.7. Statistical analysis 0.38–1.68) and according to the comparison of the curves for time to re-
mission, the protocols presented no difference (p = .55) as shown in
To analyze the association between the first-line chemotherapy Fig. 2.
treatments (8-day standard MTX/FA versus modified regimen) and In assessing the adverse events due to MTX/FA treatment for low-
each of the categorical variables, Chi-square test was used. risk GTN, no differences were observed when comparing standard treat-
To compare continuous variables among the first-line chemotherapy ment with the modified 8-day MTX/FA regimen according to Common
treatment regimens studied, the Kruskal-Wallis test was used. Terminology Criteria for Adverse Events [20], as shown in Table 4. Re-
Differences were considered statistically significant when p-values gardless of the MTX/FA regimen administered, the most prevalent ad-
were b0.05. verse events were fatigue (44.7 versus 39.7%; p = .790), dry eye (37.9
For outcomes of interest, adjusted odds ratios with 95% confidence versus 36.7%; p = .543), mucositis oral (35.1 versus 33.6%; p = .500)
intervals (95% CI) were calculated using the Wald test for logistic re- and nausea (21.9 versus 19.4%; p = .500), not differing between the
gression. Variables were selected for inclusion into the multivariate standard or modified regimens studied, respectively. It is also notewor-
model by the Akaike Information Criteria. To correct for multiple hy- thy that toxicity as a cause of MTX/FA regimen replacement was
pothesis testing, p b .01 was used as the threshold for significance in an-
alyzing. To compare the time until remission, the log-rank test was used.
Table 1
Statistical analysis was made using R software statistical package Characteristics of patients with low-risk gestational trophoblastic neoplasia treated ac-
version 3.3.2, available at www.r-project.org. cording to different methotrexate with folinic acid rescue (MTX/FA) regimens.
Variables Standard Modified p-Value

3. Results
8-day 8-day MTX/FA
MTX/FA N = 98
Fig. 1 represents a flow diagram describing the study population. N = 538
From January 1990 to December 2017, 6325 patients were diagnosed Age (years) # 26.0 25.0 0.749 K
with gestational trophoblastic disease (GTD). Among these, 5090 (20.0–32.0) (21.0–32.0)
(80.5%) achieved spontaneous remission and 1235 (19.5%) developed Gravidity # 2.0 (1.0–2.0) 2.0 (1.0–2.75) 0.217 K
GTN, among which 937 (75.8%) were categorized as low-risk GTN and Parity # 0.0 (0.0–1.0) 1.0 (0.0–1.0) 0.154 K
Antecedent pregnancy 0.221C
538 (61.5%) were treated with standard 8-day MTX/FA and 98 (11.2%) Hydatidiform mole 518 (96.3%) 90 (92.8%)
received modified 8-day MTX/FA. Complete 357 (69%) 64 (71%)
The presenting characteristics of patients with low-risk GTN treated Partial 161 (31%) 26 (29%)
with standard 8-day MTX/FA were comparable to those who received Term/Preterm gestation 1 (0.2%) 0 (0%)
Abortion 19 (3.5%) 7 (7.2%)
modified 8-day MTX/FA regimen, including age (p = .749), gravidity
Ectopic pregnancy 0 (0%) 0 (0%)
(p = .217), parity (p = .154), antecedent pregnancy (p = .221), time Time between the end of pregnancy 4 (3–5) 4 (3–5) 0.926 K
between the end of pregnancy and the initiation of chemotherapy and the initiation of chemotherapy
(p = .926) and hCG pretreatment (p = .112) (Table 1). In general (months) #
these patients were young, childless, had postmolar GTN, notably after b4 479 (89.0%) 87 (88.8%)
4–6 55 (10.2%) 10 (10.2%)
complete hydatidiform mole, whose GTN diagnosis occurred about
7–12 3 (0.6%) 1 (1.0%)
4 months after termination of pregnancy, and with most hCG pretreat- N 12 1 (0.2%) 0 (0%)
ment levels ranging from 1000 to 100,000 IU/L. hCG ⁎ (IU/L) pretreatment levels # 12,000 14,000 0.112 K
Table 2 showed that there was no increase in the prevalence of CCA (900–50,000) (4000–45,000)
b 103 70 (13.0%) 12 (12.2%)
(p = .533) and no difference in WHO/FIGO prognostic risk score (p =
103–104 190 (35.3%) 47 (47.9%)
.723) among patients with low-risk GTN treated with the two chemo- 104–105 232 (43.1%) 32 (32.6%)
therapy regimens studied. However patients who were treated with N 105 46 (8.6%) 7 (7.3%)
modified 8- day MTX/FA had twice the number of cases of metastatic # Median and interquartile range. * hCG – human chorionic gonadotropin (IU/L – Interna-
disease (22.5%) than those who received the standard 8-day MTX/FA tional units per liter).
regimen (10.6%; p = .002). K – Kruskal-Wallis test. C – Chi-squared test.
Table 2 second-line treatment, or the occurrence of relapse or death did not

Oncological profile of patients with low-risk gestational trophoblastic neoplasia treated vary.
according to different methotrexate with folinic acid rescue (MTX/FA) regimens.
Single-agent MTX therapy for low-risk GTN has been associated with
Variables Standard 8-day Modified 8-day p-Value a 65–90% remission rate, which is comparable to our 76–77% remission
MTX/FA MTX/FA rate with 8-day MTX/FA, either with the standard or the modified regi-
N = 538 N = 98
men [22–25]. Although we do not recommend the modified 8-day
Stage, n (%) 0.002C MTX/FA regimen, the efficacy and safety established with our data sug-
I 454 (84.4%) 74 (75.5%)
gest that this alternative scheme maybe reasonable if eliminating MTX
II 27 (5.0%) 2 (2.0%)
III 57 (10.6%) 22 (22.5%) administration during the weekend is necessary.
Histology of GTN 0.533C MTX is one of the most potent anticancer agents. Following its intra-
None 524 (97.4%) 96 (97.9%) muscular administration, the peak serum concentration occurs within
Invasive mole 2 (0.4%) 1 (1.0%) 30 to 60 min, with 80% bioavailability of the drug. After absorption,
Choriocarcinoma 12 (2.2%) 1 (1.1%)
Occurrence of metastasis ¥ 84 (15.6%) 24 (24.5%) 0.002C
MTX binds to plasma proteins, notably albumin. MTX metabolization
WHO/FIGO⁎ Prognostic Risk 2.0 (2.0–2.0) 2.0 (2.0–2.0) 0.723C occurs intracellularly, giving rise to its active metabolites, including
Score# MTX-polyglutamate [26]. This byproduct of MTX is trapped intracellu-
0 5 (0.9%) 0 (0%) larly, has a large molecular chain that limits efflux from the cell, and ex-
1 96 (17.8%) 14 (14.3%)
erts its metabolic action of inhibiting multiple enzymes, including
2 308 (57.2%) 60 (61.2%)
3 61 (11.3%) 14 (14.3%) dihydrofolate reductase, in a stable manner for up to 48 h after MTX ad-
4 32 (5.9%) 3 (3.1%) ministration, even after renal clearance of serum MTX [27–29]. It is pre-
5 31 (5.8%) 6 (6.2%) cisely these chemical properties and pharmacodynamics of MTX
6 5 (1.1%) 1 (0.9%) polyglutamate that may explain comparable results in primary remis-
#
Median and interquartile range. sion rate in low-risk GTN patients treated with different 8-day MTX/
¥
Metastatic GTN involving the pelvis (vagina/uterine cervix) and lung. FA regimens.
⁎WHO/FIGO – World Health Organization/International Federation of Gynecology and
Nevertheless, patients treated with modified 8-day MTX/FA re-
Obstetrics.
K – Kruskal-Wallis test. C – Chi-squared test. quired an increased total number of chemotherapy cycles to achieve re-
mission, leading to longer time to remission than those treated with
standard 8-day MTX/FA. It should be noted, however, that patients
infrequent, comparable between standard or modified regimen (9.5 treated with modified 8-day MTX/FA had twice number of cases of met-
versus 9.1%; p = .500) and no differences in severity of these events astatic lung disease as those receiving standard 8-day MTX/FA. This
were observed considering the MTX/FA regimen studied. rather than the delay in the last day of MTX treatment may explain
the need for an increased total number of chemotherapy cycles to
achieve remission in this group. Since adjusting the effect of the occur-
4. Discussion rence of lung metastases through multivariate logistic regression, it was
observed that there was no increased need to use N5 cycles of chemo-
Low-risk GTN is widely cured with single-agent chemotherapy, and therapy or more time to achieve remission in patients treated with
MTX/FA regimens were preferred as first-line treatment in the present second-line chemotherapy for low-risk GTN, regardless of the 8-day
series. No differences were observed in the primary remission rate, MTX/FA regimen previous used.
the number of cycles required for remission in first-line treatment or Data from patients treated with MTX at the New England Tropho-
even the frequency or severity of toxicities when comparing patients blastic Disease Center showed that the presence of metastasis was
treated with standard 8-day MTX/FA and those receiving modified 8- also a strong independent predictor of requiring additional cycles of
day MTX/FA regimen. Likewise, regardless of the MTX/FA regimen ad- chemotherapy (OR = 13) [24]. However, although the occurrence of
ministered, the development of chemoresistance as an indication for pulmonary metastases may worsen the prognosis of patients with
second-line chemotherapy, the need for multi-agent chemotherapy in low-risk GTN [30], this does not appear to modify the occurrence of
Table 3
Outcomes of patients with low-risk gestational trophoblastic neoplasia treated according to different methotrexate with folinic acid rescue (MTX/FA) regimens.
Variables Standard 8-day MTX/FA Modified 8-day MTX/FA p-Value

N = 538 N = 98
Remission in first-line, n (%) 412 (76.7%) 95% CI: 73.0–80.1% 76 (77.6%) 95% CI: 69.3–85.9% 0.999C
Number of cycles needed to remission in first-line W # 5.0 (4.0–5.0) 5.0 (4.0–5.0) 0.966 K
Number of cycles done before resistance in first-line # 5.0 (4.0–5.0) 5.0 (4.75–5.0) 0.417 K
Time to switch to second-line therapy (weeks) # 10.0 (8.0–10.0) 10.0 (10.0–12.0) 0.176 K
hCG (IU/L)⁎⁎ at switch to second-line therapy 9812 (1120–30,001) 22,500 (13,814–36,875) 0.535 K
Reason to switch to second-line therapy 0.500C
Chemoresistance, n (%) 114 (90.5%) 20 (90.9%)
Toxicity, n (%) 12 (9.5%) 2 (9.1%)
Remission in second line, n (%) 91 (72.2%) 12 (54.5%) 0.055C
Second line treatment, n (%) 0.084C
Single agent 98 (77.8%) 14 (63.6%)
Multiagent regimen 28 (22.2%) 8 (36.4%)
Number of cycles to remission in patients who needed second-line therapy # 5.0 (4.0–7.0) 6.0 (5.0–7.0) 0.004 K
Time to remission (weeks) # 16.0 (12.0–20.0) 19.0 (18.0–24.0) b0.001 K
Relapse, n (%) 9 (1.7%) 4 (4.1%) 0.122C
Death, n (%) 2 (0.4%) 1 (1.0%) 0.475C
W
Without consolidation.
#
⁎⁎hCG – human chorionic gonadotropin (IU/L – International units per liter).
K – Kruskal-Wallis test. C – Chi-squared test.
MTX chemoresistance [31], as shown in this paper. Frijstein et al. con-

cluded that the presence of lung metastases among patients initially
treated with MTX increases the risk of chemoresistance although it
does not decrease the overall complete response. However, the authors
highlighted that cases of low-risk choriocarcinoma patients with lung
metastases should be initially treated with a multiagent regime due to
the higher chance of chemoresistance to single-agent chemotherapy
[32]. Unfortunately, the cases of choriocarcinoma in the population
studied were too small to assess its impact on MTX treatment response.
Our study does have several limitations. The main limitation of this
study was a retrospective non-randomized comparison of these two
regimens and the small number of patients with low-risk GTN evalu-
ated. However, considering that the remission with first-line treatment
Fig. 2. Time to remission in the second-line treatment for low-risk GTN after resistance was the main response variable in this study, the results were used to
with standard or modified 8-day MTX/FA, adjusted for the occurrence of metastasis. estimate the probability of type II error as 3.91%, giving this result 96%
Table 4
Adverse events due to different methotrexate with folinic acid rescue (MTX/FA) regimens for treatment of low-risk gestational trophoblastic neoplasia, graded according to Common Ter-
minology Criteria for Adverse Events, version 5.0 (2017).
Variable Standard 8-day MTX/FA (N = 538) Modified 8-day MTX/FA (N = 98) p-Value for Adverse event p-Value for CTC grade 3 + 4
(Chi-square test) (Chi-square test)
Disorders by System Adverse CTC grade (N/%) Adverse CTC grade (N/%)
event event
1 2 3 4 1 2 3 4
N (%) N (%)
Blood
Anemia 98 (18.2) 55 25 15 3 17 (17.3) 9 5 2 1 0.525 0.500
(10.2) (4.6) (2.8) (0.6) (9.2) (5.1) (2) (1)
Febrile neutropenia 6 (1.1) – – 6 – 1 (1) – – 1 – 0.500 ⁎
(1.1) (1)
Cardiac
Chest pain 6 (1.1) – 4 2 – 1 (1) – 1 (1) – – 0.500 ⁎
(0.7) (0.4)
Eye
Dry eye 204 192 12 – – 36 (36.7) 34 2 (2) – – 0.543 ⁎
(37.9) (35.7) (2.2) (34.7)
Gastrointestinal
Mucositis oral 189 151 33 5 – 33 (33.6) 26 6 1 – 0.565 0.500
(35.1) (28.1) (6.1) (0.9) (26.5) (6.1) (1)
Nausea 118 90 22 6 – 19 (19.4) 14 4 1 – 0.666 0.500
(21.9) (16.7) (4.1) (1.1) (14.3) (4.1) (1)
Stomach pain 27 (5) 20 7 – – 4 (4.1) 3 1 (1) – – 0.556 ⁎
(3.7) (1.3) (3.1)
Vomiting 22 (4) 18 4 – – 4 (4.1) 3 1 (1) – – 0.500 ⁎
(3.3) (0.7) (3.1)
General
Fatigue 241 201 40 – – 39 (39.7) 33 6 – – 0.790 ⁎
(44.7) (37.3) (7.4) (33.6) (6.1)
Infections
Upper respiratory 20 (3.7) – 15 5 – 3 (3.1) – 2 (2) 1 – 0.510 0.500
(2.8) (0.9) (1)
Urinary tract 5 (0.9) – 5 – – 1 (1) – 1 (1) – – 0.500 ⁎
(0.9)
Vaginal 15 (2.7) 13 2 – – 2 (2) 2 (2) – – – 0.532 ⁎
(2.3) (0.4)
Investigations
Aspartate 38 (7) 31 6 1 – 7 (7.1) 5 2 (2) – – 0.500 ⁎
aminotransferase ↑ (5.7) (1.1) (0.2) (5.1)
Lymphocyte count ↓ 80 (14.8) 52 22 6 – 13 (13.2) 8 4 1 – 0.602 0.500
(9.6) (4.1) (1.1) (8.1) (4.1) (1)
Neutrophil count ↓ 35 (6.5) 20 9 6 6 (6.1) 4 1 (1) 1 – 0.500 0.500
(3.7) (1.7) (1.1) (4.1) (1)
Platelet count ↓ 35 (6.5) 20 9 6 6 (6.1) 4 1 (1) 1 0.500 0.500
(3.7) (1.7) (1.1) (4.1) (1)
Reproductive
Irregular 32 (5.9) 26 6 – – 6 (6.1) 5 1 (1) – – 0.500 ⁎
menstruation (4.8) (1.1) (5.1)
Menorrhagia 22 (4) 18 2 2 4 (4.1) 3 1 (1) – – 0.500 ⁎
(3.2) (0.4) (0.4) (3.1)
Respiratory
Pleuritic pain 34 (6.3) 15 14 5 – 6 (6.1) 3 2 (2) 1 – 0.500 0.500
(2.8) (2.6) (0.9) (3.1) (1)
Skin
Photosensitivity 14 (2.6) 7 (1.3) 4 3 – 3 (3.1) 3 – – – 0.500 ⁎
(0.7) (0.6) (3.1)
⁎ Numbers too small to compare.
power. Additionally, data was collected from a GTN-RC and may not re- Declaration of competing interest
flect the outcomes that could be seen the Brazilian general population or
patients with GTN with different nationalities or ethnicities. Although The authors declare no conflict of interests.
logistic regression excluding the effect of pulmonary metastasis occur-
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UNIVERSIDADE FEDERAL FLUMINENSE FACULDADE DE MEDICINA

PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS MÉDICAS

PAULO ALEXANDRE RIBEIRO MORA

AVALIAÇÃO DA UTILIZAÇÃO DE CARBOPLATINA OU ETOPOSIDE EM

AVALIAÇÃO DA UTILIZAÇÃO DE CARBOPLATINA OU ETOPOSIDE EM

Tese submetida ao Programa de Pós-Graduação

Orientador: Prof. Dr. ANTÔNIO RODRIGUES BRAGA NETO

AVALIAÇÃO DA UTILIZAÇÃO DE CARBOPLATINA OU ETOPOSIDE EM

Tese submetida ao Programa de Pós-Graduação

Ao meu orientador Antônio Rodrigues Braga Neto, pela confiança, conhecimento

Figura 1 - Diagrama resumindo a divisão da população do estudo 35

Tabela 1 - Estadiamento e Classificação da FIGO/OMS para Neoplasia 20

Tabela 2 - Taxas de remissão primária na Neoplasia Trofoblástica Gestacional de 22

Tabela 3 - Características dos pacientes com neoplasia trofoblástica gestacional 36

Tabela 4 - Perfil clínico e terapêutico de pacientes com falha ao MTX/AF para o 37

Tabela 5 - Desfechos dos esquemas de tratamento de segunda linha de pacientes 39

Tabela 6 - Eventos adversos secundários ao regime de segunda linha para o 41

Tabela 7 - Comparação Indireta de Dados entre os Estudos de Carboplatina em 44

AUC Area Under Curve (Área Sob a Curva)

COI Clínicas Oncológicas Integradas (Oncologia Américas)

CTC Common Toxicity Criteria (Critério Comum de Toxicidade)

CTCAE Common Terminology Criteria for Adverse Events (Critério Comum de

DTG Doença Trofoblástica Gestacional

EMA-CO Etoposide, Metotrexato, Actinomicina D, Ciclofosfamida e Vincristina

FIGO International Federation of Gynecology and Obstetrics (Federação

G-CSF Granulocyte-colony stimulating factor (Fator de estimulação de colônias de

GFR Glomerular Filtration Rate (Taxa de Filtração Glomerular)

hCG Gonadotrofina Coriônica Humana

HCII Hospital do Câncer Unidade II (INCA)

HTA Histerectomia Total Abdominal

INCA Instituto Nacional de Câncer

mmHg Milímetros de Mercúrio

NTG Neoplasia Trofoblástica Gestacional

OMS Organização Mundial da Saúde

RCOG Royal College of Obstetricians and Gynaecologists (Colégio Inglês de

RNM Ressonância Nuclear Magnética

TE/TP Paclitaxel-Etoposide e Paclitaxel-Cisplatina

TGO Transaminase glutâmico oxaloacética/aspartato aminotransferase (AST)

TGP Transaminase glutâmico pirúvica/alanina aminotrasnferase (ALT)

TTE Tumor Trofoblástico Epitelioide

TTSP Tumor Trofoblástico do Sítio Placentário

UFF Universidade Federal Fluminense

UFRJ Universidade Federal do Rio de Janeiro

UI/L Unidades Internacionais por Litro

USTV Ultrassonografia Transvaginal

A neoplasia trofoblástica gestacional (NTG) é o termo utilizado para designar lesões

Em geral, a NTG é altamente responsiva à quimioterapia e possui um marcador

1.1 Classificação e Estadiamento

Ao longo do tempo, diversos estadiamentos, classificações e sistemas prognósticos

(MTX/FA) ou actinomicina-D (Act-D), com taxas de remissão primária variando de 70 a 90%

Tabela 1 – Estadiamento e Classificação da FIGO/OMS para Neoplasia Trofoblástica

NTG: estadiamento e classificação FIGO (Washington, 2000)

Sistema de escore prognóstico da OMS modificado pela FIGO

1.2 Tratamento Sistêmico

Há 50 anos, antes da introdução da QT no manejo da NTG, a taxa de mortalidade por

A tabela 2 mostra as taxas de remissão primária de acordo com o regime de QT utilizado

Tabela 2 – Taxas de remissão primária na Neoplasia Trofoblástica Gestacional de baixo risco

1.3 Tratamento da NTG com quimiorresistência ao MTX

Trofoblástica Gestacional, pela Federação Brasileira das Associações de Ginecologia e

2.1 Desenho do Estudo

Este é um estudo de coorte retrospectivo colaborativo de pacientes com NTG

2.2 Participantes do estudo

Na publicação de Winter e colaboradores (2016) a taxa de resposta completa à

2.4 Diagnóstico de NTG